Abstract IL-17 signaling contributes to the pathogenesis of psoriasis; however, IL-17 involvement in keratinocyte hyperactivation of epidermis remains unclear. Here, we describe an IL-17A-induced, skin-specific, positive feedback loop, which operates independently of canonical chemokine production, thus untangling skin inflammation and epithelial hyperproliferation in psoriasis. We show that IL-17A-induced, keratinocyte-specific KLK8 interacts with IL-17R to promote histone H4 lysine lactylation (H4K12la) catalyzed by the acetyltransferase HAT1. H4K12la further promotes IL-17A-mediated keratinocyte proliferation and the expression of KLK8 and IL-17R, creating a feedback loop that drives psoriasis progression. Importantly, excessive lactate in the microenvironment exacerbates H4K12la and psoriasis severity, thereby impairing the efficacy of anti-IL-17A antibody. Silencing KLK8, HAT1, or inhibiting lactate accumulation attenuates psoriasis in mice. Moreover, combining lactylation inhibition with anti-IL-17A therapy exhibits synergistic effects against antibody-resistant psoriasis. Thus, our findings unveil a lactylation-driven, keratinocyte-specific IL-17A signaling and offer a promising approach for psoriasis treatment, particularly in patients with comorbid metabolic syndrome. Subject terms: Immunological disorders, Post-translational modifications, Immunological disorders __________________________________________________________________ IL-17A signaling contributes to the pathogenesis of psoriasis via the production of inflammatory mediators. Here, by integrating in vitro experiments and in vivo analysis, the authors report a non-canonical IL-17-KLK8 axis that induces lactate accumulation and histone lactylation, ultimately driving keratinocyte hyperactivation, and highlight the therapeutic value of targeting this lactylation-driven pathway for psoriasis treatment. Introduction Despite the critical role of interleukin-17 (IL-17) signaling in a variety of diseases, including rheumatoid arthritis, multiple sclerosis, and Crohn’s disease^[38]1–[39]4, resistance to anti-IL-17 therapies is commonly observed, with very few exceptions, such as psoriasis^[40]5. Our previous study unveils a mechanism referred to as the ‘backdoor’ due to its concealment in IL-17A-induced signaling, wherein IL-17A induces high levels of tyrosine phosphatase SHP2, sustaining inflammation through autonomous activation of IL-17R signaling independent of IL-17A stimulation, thus leading to resistance against anti-IL-17A therapy^[41]6. These findings provide evidence of how inflammation can sustain autonomously and shed light on the reasons behind the resistance observed in certain IL-17A-related diseases towards anti-IL-17A therapy. However, the precise mechanisms by which IL-17A uniquely drives the pathogenesis of these diverse diseases remain largely unknown. Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation of keratinocytes and marked inflammation, and scaly erythematous plaque^[42]7,[43]8. Infiltrating inflammatory cells and pro-inflammatory cytokines play important roles in the pathogenesis of psoriasis, thereby facilitating the development of multiple targeted therapies, including anti-IL-17/IL-17R antibodies^[44]5,[45]9,[46]10. IL-17A acts on various cell types in the skin, particularly keratinocytes, contributing to both the early onset and chronic maintenance of psoriasis^[47]11. Classically, IL-17A induces IL-17R/Act1 complex to activate downstream NF-κB and MAPK signaling pathways^[48]12,[49]13, leading to production of various pro-inflammatory cytokines, chemokines, and antimicrobial peptides in keratinocytes, as a fundamental mechanism in psoriasis-associated skin inflammation^[50]14. In addition to skin inflammation, psoriatic skin exhibits disrupted epidermal barrier integrity, acanthosis, parakeratosis, and scale formation^[51]15, which are closely associated with IL-17A. Neutralizing IL-17A using ixekizumab or secukinumab in psoriasis patients significantly reduces histopathological features of epidermal acanthosis, elevated numbers of proliferating keratinocytes, and keratin 16 expression^[52]16,[53]17. Imiquimod-induced epidermal thickness in a mouse model of psoriasis is significantly reduced in keratinocyte-specific IL-17RA-deficient mice^[54]18. Thus, the role of IL-17A signaling in inflammatory factors production seems insufficient to fully explain the excessive activation of keratinocytes, suggesting the existence of another aspect of IL-17A signaling in the pathogenesis of psoriasis. However, the detailed molecular mechanisms remain largely unknown. In this study, we report a skin tissue-specific IL-17 signaling pathway independent of canonical chemokine production. This non-canonical IL-17-dependent signaling involves IL-17RA/KLK8 interaction, lactate production, and histone H4 lysine 12 lactylation (H4K12la), and subsequent cell cycle gene expressions, leading to the hyperactivation of keratinocytes. Moreover, the excessive activation of this non-canonical IL-17A signaling, driven by elevated environmental lactate from multiple cellular sources, reduced the efficacy of anti-IL-17A therapy against psoriasis. This study provides insights into the distinction between skin inflammation and epithelial hyperactivation in psoriasis, emphasizing the role of KLK8-mediated regulation of IL-17 signaling. It also highlights the therapeutic potential of targeting H4K12la for psoriasis treatment. Results Keratinocyte-specific KLK8 is essential for sustained keratinocyte hyperactivation and psoriasis progression, regardless of the downstream chemokines of IL-17A signaling We have previously reported that autonomous activation of IL-17R signaling mediated by increased SHP2 expression sustains inflammation and nullifies anti-IL-17A efficacy^[55]6. However, despite the upregulation of SHP2 in skin samples of psoriatic patients, they do exhibit a positive response to anti-IL-17 therapies. Psoriasis is characterized by persistent inflammation and aberrant keratinocyte hyperproliferation, supported by gene analysis showing enrichment in the cell cycle and IL-17 signaling pathways (Supplementary Fig. [56]1a). Interestingly, our study demonstrated that SHP2 overexpression in keratinocytes mainly contributed to the abundance of chemokines, rather than the key pathological change of sustained cell hyperproliferation and migration (Supplementary Fig. [57]1b–d). A clinical study further identified increased expression of genes related to cell cycle and keratinocyte function in individuals with weak response to immunomodulatory agents for inflammatory skin diseases^[58]19. Based on these findings, we propose that the IL-17A pathway in psoriatic keratinocytes may carry a distinct pattern for the pathogenesis of psoriasis. To unravel this, we analyzed microarray data from skin biopsies of patients with moderate-to-severe psoriasis. KEGG pathway analysis revealed that genes up-regulated in psoriatic lesions but failed to revert following etanercept treatment, a biologic TNF inhibitor approved for the treatment of moderate to severe plaque psoriasis^[59]10,[60]20, were enriched in IL-17 pathway (Supplementary Fig. [61]1e). Four IL-17RA-binding molecules were chosen from the related genes, following a comparison with a published molecular database (Supplementary Fig. [62]1f). Among these four genes, only KLK8, encoding kallikrein related peptidase 8 (KLK8), was identified as a skin-specific molecule^[63]21. We confirmed that KLK8 was primarily expressed in human and mouse skin tissues, with nearly exclusive expression in skin keratinocytes (Supplementary Fig. [64]1g–i). Protein docking predictions revealed the binding of KLK8 to the transmembrane region of IL-17RA (Supplementary Fig. [65]2a). It interacted with IL-17RA in HEK293T cells exogenously transfected with Flag-IL-17RA and Myc-KLK8 (Supplementary Fig. [66]2b–d). More importantly, the expression of KLK8 was significantly increased in keratinocytes of skin tissues from psoriasis patients (Fig. [67]1a–c and Supplementary Fig. [68]2e) and imiquimod-induced psoriatic mice (Fig. [69]1d and Supplementary Fig. [70]2f, g), and positively correlated with the PASI score in etanercept-non-responding psoriasis patients (Supplementary Fig. [71]2h). In responsive patients, KLK8 expression was significantly reduced after treatment to levels comparable to normal skin, whereas in non-responding patients, it only partially decreased and remained significantly higher than in normal skin (Supplementary Fig. [72]2i). We then stimulated HaCaT cells with IL-17A and observed a time-dependent increase in both gene and protein levels of KLK8 (Supplementary Fig. [73]2j–l). In contrast, other inflammatory cytokines (TNF, IL-6, IL-17E, and IFN-γ) had minimal impact on KLK8 expression, except for a mild increase observed with TNF (Supplementary Fig. [74]2m). Moreover, anti-IL-17A antibody GR1501 specifically suppressed IL-17A-induced KLK8 upregulation, whereas etanercept did not inhibit TNF-induced KLK8 expression (Supplementary Fig. [75]2n). Similarly, both secukinumab and anti-mIL-17A antibody greatly inhibited KLK8 expression in the skin of psoriatic patients and mice, respectively (Fig. [76]1e, f and Supplementary Fig. [77]2o). These findings may explain why anti-IL-17 antibodies are more effective than anti-TNF antibodies in the clinical treatment of psoriasis^[78]20 and highlight the specific induction of KLK8 by IL-17A in keratinocytes, suggesting its unique role in psoriasis. Fig. 1. Keratinocyte-specific KLK8 maintains IL-17A-induced cell proliferation and migration independent of chemokine production. [79]Fig. 1 [80]Open in a new tab a, b Representative spatial transcriptomics plots (a) and UMAP plots (b) of healthy donor and psoriasis patient skin tissues, with feature plots of KLK8 and corresponding cluster annotation. c, d Representative skin tissues immunofluorescence of KLK8 (red) and KRT14 (green) in healthy donors and psoriasis patients (c) or normal and IMQ-induced psoriatic mice (d). n  =  5 per group. “Epi” stands for the epidermis and “dermis” for the dermis. Scale bar: 50 μm. e Violin plot of KLK8 expression in healthy donors and psoriasis patients skin tissues before and after treatment with anti-IL-17A monoclonal antibody secukinumab. f KLK8 expression in whole dorsal skin tissues from imiquimod-induced psoriasis mice and psoriasis mice treated with anti-mIL-17A antibody. n  =  8 mice per group. g, h Violin and UMAP plots illustrate the segregation of keratinocytes from psoriasis patients into KLK8 low (KLK8 low) and high (KLK8 high) expression clusters (g) and their Reactome pathway enrichment analysis (h). i, j HaCaT cells were transfected with si-Ctrl or si-KLK8 and stimulated with 50 ng/mL IL-17A. i Cell viability. n = 3 experiments. j The mRNA levels of the indicated genes. n  =  4 experiments. k–n The mice were injected with an adenovirus that specifically targets keratinocytes (AAV-Krt14), either carrying a negative control shRNA (sh-NC) or a Klk8 shRNA (sh-Klk8). k Skin tissues harvested from each group of mice on day 5 were analyzed by H&E. Scale bar: 50 μm. l Skin thickness. m The daily PASI score. n The protein expression levels of KLK8 and PCNA in whole skin tissues. n = 5 (Con, IMQ+Krt14-sh-Klk8), n = 6 (IMQ+Krt14-sh-NC). o The mRNA levels of Klk8, Mki67 and Pcna in whole skin tissues. n  = 5 mice per group. Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001; ns, not significant. Statistical analysis was performed using two-tailed unpaired Student’s t tests (f, i, j, and l–o). Source data are provided as a Source Data file. To further investigate the role of KLK8 in psoriatic keratinocytes, we preformed classification of keratinocytes in psoriasis patients based on their levels of KLK8 expression, resulting in the identification of two distinct populations: a population with low KLK8 expression (KLK8 low) and a population with high KLK8 expression (Fig. [81]1g). Further analysis using cellular pathway enrichment revealed that the KLK8 high population was primarily associated with cell cycle regulation, in contrast to the KLK8 low population (Fig. [82]1h). In vitro experiments confirmed that KLK8 knockdown in HaCaT cells significantly inhibited IL-17A-induced proliferation and migration (Fig. [83]1i and Supplementary Fig. [84]3a–d), but did not affect the expression of chemokines, cytokines and antimicrobial peptides downstream of the classical IL-17 pathway (Fig. [85]1j), while overexpression increased the percentage of cells in the S and G2M phases (Supplementary Fig. [86]3e). Subsequently, we topically applied gel emulsifier containing si-Klk8 to the back of imiquimod-induced psoriasis mice and found that treatment with si-Klk8 significantly suppressed psoriasis progression (Supplementary Fig. [87]4a–i). To specifically silence KLK8 in skin keratinocytes, we utilized the adeno-associated virus (AAV)-promoter of Krt14-shKlk8 (Supplementary Fig. [88]4j–l). This targeted knockdown led to notable reductions in clinical scores and epidermis thickness, while also inhibiting inflammation, tissue destruction, and the expression of proliferation-related molecules (Fig. [89]1k–o and Supplementary Fig. [90]4m). However, it did not reduce the expression of pro-inflammatory factors downstream of the classical IL-17A signaling pathway in the epidermal layer (Supplementary Fig. [91]4n), which was consistent with our in vitro findings in Fig. [92]1j. These results suggest that KLK8 regulates psoriasis progression predominantly by orchestrating IL-17A-mediated proliferation and migration of keratinocytes, independent of the classical downstream chemokines production. Therefore, despite the upregulation of classical chemokines in psoriasis, inhibiting KLK8 expression with anti-IL-17A antibodies successfully attenuates the hyperactivation of keratinocytes. KLK8 governs lactate production and transport in psoriatic keratinocytes To further elucidate the regulatory mechanisms of KLK8 on IL-17A-stimulated keratinocytes, we analyzed single-cell RNA sequencing data (scRNA-seq) from psoriasis patients and IMQ-induced psoriatic mice. Our analysis revealed the enrichment of the HIF-1 signaling pathway and glycolysis in psoriatic keratinocytes (Fig. [93]2a, b and Supplementary Fig. [94]5a–d). HIF1A and enzymes related to the glycolytic pathway (LDHA, PGK1, ALDOA, HK2, and TPI1) were significantly elevated in skin tissues of psoriasis patients and mice, whereas HIF1A’s inhibitor HIF1AN showed marked downregulation (Supplementary Fig. [95]5e–h). We then performed high-throughput metabolomics on the culture medium of IL-17A-stimulated HaCaT cells after KLK8 knockdown. Notably, we found that IL-17A induced lactate production in cells to a greater extent compared to other metabolites, and this effect was significantly suppressed by KLK8 knockdown (Fig. [96]2c, d, and Supplementary Fig. [97]5i, j). Besides, IL-17A increased expression of the lactate transporter MCT1 (encoded by SLC16A1) (Fig. [98]2e, f), which was suppressed by anti-IL-17A antibody GR1501 (Supplementary Fig. [99]6a). Consistent with these findings, elevated expression of MCT1 was observed in psoriatic patients (Fig. [100]2g, h) and mice (Fig. [101]2i–k), particularly in psoriatic keratinocytes (Supplementary Fig. [102]6b, c). Furthermore, SLC16A1 expression correlated with PASI scores in patients who did not respond to etanercept treatment (Supplementary Fig. [103]6d). Moreover, specific knockdown of KLK8 in keratinocytes almost completely suppressed lactate levels in skin tissues and serum of IMQ-induced psoriasis mice (Fig. [104]2l–n), suggesting that keratinocytes are likely the main contributors to lactate production through the activity of KLK8. This knockdown also reduced the expression of key enzymes in the glycolytic pathway in IL-17A-treated HaCaT cells and skin tissues of IMQ-induced psoriasis mice (Fig. [105]2o, p). These observations were further supported by the pronounced correlation between KLK8 and these genes in psoriasis patients (Fig. [106]2q). These findings underline the critical involvement of KLK8 in regulating glucose metabolism and lactate transport specifically within psoriatic keratinocytes. Fig. 2. KLK8 governs lactate production and transport in psoriatic keratinocytes. [107]Fig. 2 [108]Open in a new tab a, b Unbiased clustering of human (above) and imiquimod-induced mice (below) skin scRNA data shown by UMAP plots (a), and the KEGG pathway enrichment of upregulated genes in both human and imiquimod-induced mouse psoriatic skin keratinocytes (p < 0.05, log[2]Fc > 0.9) (b). c The HaCaT cells were transfected with si-NC and si-KLK8, followed by 50 ng/mL IL-17A induction for 24 h, and then the cell supernatants were collected for targeted metabolomics sequencing. n = 3 per group. d Extracellular lactate levels of HaCaT cells stimulated with 50 ng/mL IL-17A for 24 h after KLK8 knockdown. n = 4 experiments. e, f SLC16A1 expression in HaCaT cells stimulated with 50 ng/mL IL-17A for 24 h were measured by qPCR (e) and immunoblotting (f). n = 3 experiments. g The SLC16A1 mRNA in skin tissues of control subjects (n = 64) and psoriasis patients (n = 58). h, i MCT1 expression in skin tissues from psoriasis patients (h) and imiquimod-induced psoriatic mice (i). n  = 5 per group. “Epi” stands for the epidermis and “dermis” for the dermis. Scale bar: 100 μm. j, k The mRNA level of Slc16a1 (j), and the protein levels of MCT1 and PCNA (k) from control and psoriatic mice. n  = 8 mice per group. l Lactate levels in the mice skin tissues. n  = 5 mice per group. m Lactate levels in the mice skin tissues. n = 5 (Con, IMQ+Krt14-sh-Klk8), n = 6 (IMQ+Krt14-sh-NC). n Lactate levels in the mice serum. n  = 5 mice per group. o The related mRNA levels in HaCaT cells stimulated with 50 ng/mL IL-17A for 24 h after KLK8 knockdown. n = 3 experiments. p The levels of the related mRNA in the skin tissue of each group of mice. n  = 5 mice per group. q Correlations between KLK8 and LDHA, PGK1, ALDOA, HK2, TPI1 and SLC16A1 expressions. “NN”, normal skin (n = 64), “PN”, psoriasis non-lesional skin (n = 64), “PP”, psoriasis lesional skin (n = 58). Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001; ns, not significant. Statistical analysis was performed using a hypergeometric test (b), two-tailed unpaired Student’s t tests (d, e, and j–p), one-way ANOVA (g), or two-tailed Pearson’s correlation analysis (q). Source data are provided as a Source Data file. In addition, the production of lactate induced by IL-17A was also reduced after knockdown of SLC16A1 or inhibition of MCT1 with the inhibitor AZD3965 in HaCcaT cells (Supplementary Fig. [109]6e, f). Meanwhile, si-SLC16A1 or AZD3965 significantly blocked IL-17A-induced keratinocyte proliferation and migration (Supplementary Fig. [110]6g–l). Treatment with AZD3965 also displayed significant inhibition against imiquimod-induced psoriasis, including reductions in skin thickness, lactate levels, and inflammatory factor production in the skin lesions (Supplementary Fig. [111]6m–r). Excessive lactate accumulation fuels psoriasis progression and resistance to anti-IL-17A antibody, which can be reversed with combination therapy Clinical data indicate a frequent association between psoriasis and metabolic disorders, including an increased susceptibility to obesity and diabetes mellitus^[112]22–[113]24. Patients with metabolic syndrome (MetS) tend to have a reduced response to anti-IL-17A antibodies and have been reported to have significantly elevated levels of lactate in skin tissue and serum^[114]22,[115]25,[116]26, suggesting the potential involvement of lactate overproduction from multiple sources within the disease microenvironment. To replicate this, we established a psoriasis model using type 2 diabetic ob/ob mice. Compared to wild-type mice, IMQ-induced ob/ob mice exhibited increased body weight and blood glucose level (Fig. [117]3a, b). These mice displayed more severe dorsal skin lesions and increased skin thickness, along with a significantly diminished response to anti-mIL-17A antibody administration (Fig. [118]3c–e). In psoriatic wildtype mice, elevated lactate levels in serum and epidermis skin tissues (Fig. [119]3f, g), as well as increased skin expression of MCT1 and KLK8 (Fig. [120]3h), were observed, which were reduced after anti-mIL-17A antibody treatment. These elevations were particularly pronounced in ob/ob psoriatic mice, but the suppressive effect of anti-mIL-17A antibody was almost attenuated (Fig. [121]3c–e). In addition, we examined single-cell data obtained from the forearm skin of normal individuals and patients with diabetes. We observed that KLK8 exhibited significantly higher expression levels in keratinocytes from the diabetic forearm skin (Fig. [122]3i, j), suggesting that KLK8 and its regulated lactate have the potential to influence the efficacy of anti-IL-17A therapies for treating psoriasis, particularly in individuals with comorbid metabolic diseases. Fig. 3. The efficacy of anti-mIL-17A monoclonal antibodies is weakened in ob/ob psoriatic mice. [123]Fig. 3 [124]Open in a new tab a, b Psoriasis model was induced in wild-type mice and ob/ob mice using imiquimod cream. a The daily weight. b The changes of fasting blood glucose concentrations were monitored on days 0, 2, and 5. n  =  5 mice per group. c–h Psoriasis model was induced in wild-type and ob/ob mice using imiquimod cream. The anti-mIL-17A antibody was given s.c. the day before day 0 and again on day 2. c Skin tissues harvested from each group of mice on day 5 were analyzed by H&E. Scale bar: 100 μm. d The daily PASI score. e Skin thickness. f, g Lactate levels in mice serum (f) and the epidermal layer of skin tissues (g). h KLK8 and MCT1 expression in whole skin tissues. n  = 5 mice per group. i Unbiased clustering of forearm skin samples from normal and diabetic subjects by UMAP plot. j The expression levels of KLK8 and marker genes in different cell populations were shown by a violin plot. Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001; ns, not significant. Statistical analysis was performed using two-tailed unpaired Student’s t tests (b, d, and e–g). Source data are provided as a Source Data file. To further explore how the environmental lactate acts on psoriatic keratinocytes, we supplemented lactate to the cell culture medium in vitro. The addition of lactate increased its content in both the cytoplasm and culture medium (Fig. [125]4a), which almost completely antagonized the inhibitory effects of anti-IL-17A antibody on keratinocyte proliferation (Fig. [126]4b), migration (Fig. [127]4c), and expression of inflammatory factors (Fig. [128]4d). Next, we administered lactate to imiquimod-induced psoriasis mice. Interestingly, we found that both subcutaneous and intradermal supplementation of lactate exacerbated skin inflammation (Fig. [129]4e, f, and Supplementary Fig. [130]7a) and increased epidermal thickness (Fig. [131]4g), with comparable efficacy between the two administration routes. Lactate levels were significantly elevated in the epidermis and dermis of psoriatic mice, particularly in the epidermis, with subcutaneous and intradermal injections further increasing lactate accumulation, the latter resulting in slightly higher lactate levels in the epidermis compared to subcutaneous injection (Fig. [132]4h). Notably, the additional administration of lactate reduced the efficacy of anti-mIL-17A antibody in ameliorating psoriasis (Fig. [133]4i, j), as evidenced by increased epidermal thickness (Fig. [134]4k), elevated lactate levels (Fig. [135]4l), and enhanced expression of inflammatory and proliferative genes in the skin tissues (Supplementary Fig. [136]7b). Taken together, these findings demonstrate that excess lactate produced from multiple cellular sources within skin microenvironment determines disease progression and resistance against anti-IL-17A therapy. Fig. 4. Lactate accumulation exacerbates psoriasis progression and impairs anti-IL-17A antibody efficacy. [137]Fig. 4 [138]Open in a new tab a–c HaCaT cells stimulated with 50 ng/mL IL-17A were treated with 10 μg/mL GR1501 for 24 h, with or without 10 mM sodium lactate. a Intracellular (left) and extracellular (right) lactate levels. n = 3 experiments. b Cell viability. n = 4 experiments. c Migration ability. n = 3 experiments. d The indicated mRNA levels. n = 3 experiments. e–h Mice were induced with imiquimod cream. Nala was injected s.c. or i.d. one day beforehand and then once a day. e Mice skin tissues on day 4 were analyzed by H&E. Scale bar: 100 μm. f The daily PASI score. g Skin thickness. h Lactate levels in the skin epidermal (Epi) or dermal (Dermis) layers. n  = 5 mice per group. i–m Mice were induced with imiquimod cream. Nala was injected s.c. one day beforehand and then once a day. The anti-mIL-17A antibody was given s.c. the day before day 0 and again on day 2. i Mice skin tissues on day 4 were analyzed by H&E. Scale bar: 100 µm. j The daily PASI score. k Skin thickness. l Lactate levels. n  = 5 mice per group. m HaCaT cells stimulated with 50 ng/mL IL-17A were treated with 10 μg/mL GR1501 for 24 h in the presence or absence of 10 mM sodium lactate, and 10 μM AZD3965 was used in combination with GR1501. The intracellular lactate content was detected. n = 4 experiments. n–q Mice were induced with imiquimod cream. Nala was injected i.d. one day beforehand and then once a day. The anti-mIL-17A antibody was given s.c. the day before day 0 and again on day 2. MCT1 inhibitor AZD3965 was injected i.p. beforehand and then once a day. n Mice skin tissues on day 4 were analyzed by H&E. Scale bar: 100 μm. o The daily PASI score. p Skin thickness. q Lactate levels in skin epidermal (left) and dermal layers (right). n  = 5 mice per group. Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001; ns, not significant. Statistical analysis was performed using two-tailed unpaired Student’s t tests (a–d, f–h, j–m, and o–q). Source data are provided as a Source Data file. Given that elevated environmental lactate levels compromise the therapeutic efficacy of anti-IL-17A monoclonal antibodies, we explored whether inhibiting lactate transport could restore efficacy. The increased cytoplasmic lactate content was significantly attenuated by treatment with the MCT1 inhibitor AZD3965 (Fig. [139]4m), indicating that it inhibited the transport of lactate into cells under high extracellular lactate conditions. We then combined AZD3965 with anti-mIL-17A antibody treatment in lactate-administered psoriasis mice. The impaired efficacy of anti-mIL-17A antibody caused by elevated lactate levels was significantly improved by AZD3965 administration, regardless of whether lactate was administered via intradermal (Fig. [140]4n–q) or subcutaneous injection (Supplementary Fig. [141]7c–f). This suggests promising potential for the clinical application of MCT1 inhibitors in treating psoriasis patients with obesity or abnormal lactate metabolism. IL-17A increases H4K12la modification in psoriatic keratinocytes in a KLK8-dependent manner The functional significance of lactate as a metabolic waste product remains overlooked until the discovery of histone lactylation, a newly identified epigenetic modification derived from lactate^[142]27,[143]28. Considering that KLK8 promotes lactate production and transport, we set out to determine whether the accumulation of lactate induces lactylation in psoriatic keratinocytes. The expression of pan-lactylation was significantly increased in skin lesions of imiquimod-induced mice (Supplementary Fig. [144]8a, b) and IL-17A-induced HaCaT cells (Supplementary Fig. [145]8c). In addition, lactate levels were significantly correlated with IL-17A but not with CXCL1 in skin tissues (Fig. [146]5a). The correlation between pan-lactylation and IL-17A was also confirmed (Fig. [147]5b). The observed augmentation of pan-lactylation in psoriatic mice, particularly near the 17 kDa position, suggests a potential association with histones. Using an alkylated lactate probe for click chemistry (Fig. [148]5c), we observed a notable upregulation of histone H4 lactylation in HaCaT cells (Fig. [149]5d and Supplementary Fig. [150]8d). Notably, only the lactylation of histone H4 lysine 12 (H4K12la) was significantly up-regulated in IL-17A-stimulated HaCaT cells and skin epidermal keratinocytes of imiquimod-induced psoriatic mice (Fig. [151]5e–h and Supplementary Fig. [152]8e–g). The upregulation of H4K12la expression was then confirmed in human psoriatic skin tissues (Fig. [153]5i) and IL-17A-stimulated keratinocytes (Supplementary Fig. [154]8h). As expected, the silencing of KLK8 effectively suppressed the IL-17A-induced increases in H4K12la levels in human primary keratinocytes and HaCaT cells (Fig. [155]5j, k and Supplementary Fig. [156]8i). In addition, both in vitro and in vivo, treatment with anti-IL-17A antibody resulted in a reduction of H4K12la expression, whereas the addition of lactate counteracted this inhibitory effect (Fig. [157]5l, m). Similarly, the H4K12la expression in mice with psoriasis was significantly inhibited when treated with the MCT1 inhibitor AZD3965 (Fig. [158]5n). Gel encapsulating si-Klk8 and intradermal injection of a keratinocyte-specific Klk8 knockdown adenovirus also effectively suppressed H4K12la expression (Fig. [159]5o, p). These results suggest that H4K12la induced by IL-17A is dependent on KLK8, which may be a key event in the keratinocyte activation and psoriasis progression. Fig. 5. IL-17A stimulates KLK8-dependent histone hyperlactylation in psoriatic keratinocytes. [160]Fig. 5 [161]Open in a new tab a Correlations between lactate and IL-17A (left) or CXCL1 (right) levels in skin tissues of control (n  = 5) and IMQ-induced psoriasis model (n  = 5). b Correlation between pan-Kla and IL-17A content in control (n  = 5) and IMQ-induced psoriatic skin tissues (n  = 5). c Diagram showing how to perform click chemistry experiments. d The probe-labeled proteins were collected for immunoprecipitation and immunoblotting. n = 3 experiments. e The expressions of different lactylation sites of histone H4 (K5, K8, K12, K16) in HaCaT cells. n = 3 experiments. f, g H4K12la expression in whole skin tissues from control and IMQ-induced psoriasis mice were measured by immunofluorescence (f) (n  = 5 mice per group) and immunoblotting (g) (n  = 8 mice per group). Scale bar: 100 μm. h, i H4K12la expression in skin tissues from imiquimod-induced psoriatic mice (h) and psoriasis patients (i) were measured by immunohistochemistry. n  = 5 per group. “Epi” stands for the epidermis and “dermis” for the dermis. Scale bar: 100 μm. j Human primary keratinocytes (KCs) were transfected with si-NC or si-KLK8, and then stimulated with 50 ng/mL IL-17A for the detection of H4K12la expression. n = 3 experiments. k HaCaT cells stimulated with 50 ng/mL IL-17A were treated with 10 μg/mL GR1501 for 24 h in the presence or absence of 10 mM sodium lactate, and then collected for detection of H4K12la expression. n = 3 experiments. l, m H4K12la expression in whole skin tissues from the indicated mice group were measured by immunoblotting (l) and immunohistochemistry (m). Scale bar: 100 μm. n  = 5 mice per group. n H4K12la expression in whole skin tissues from normal mice, psoriatic mice and AZD3965-treated psoriatic mice. n  = 5 mice per group. o H4K12la expression in whole skin tissues from control mice (n  = 5), si-Ctrl-treated psoriatic mice (n  = 5) and si-Klk8-treated psoriatic mice (n  = 6). p H4K12la expression in whole skin tissues from control mice (n  = 5), AAV-sh-NC-treated psoriatic mice (n  = 6) and AAV-sh-Klk8-treated psoriatic mice (n  = 5). Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001. Statistical analysis was performed using two-tailed unpaired Student’s t tests (f, g, l, and n–p) or two-tailed Pearson’s correlation analysis (a and b). IL-17A constructs a positive feedback loop of KLK8/IL-17R/H4K12la/cell cycle genes in keratinocytes to drive the progression of psoriasis Using H4K12la-targeted CUT&Tag-seq analysis (Supplementary Fig. [162]9a, b), we identified three distinct clusters of H4K12la-binding peaks in IL-17A-stimulated HaCaT cells (Fig. [163]6a). Approximately 42% of higher H4K12la-binding peaks were located in the promoter region (Fig. [164]6b). Pathway enrichment analysis revealed that the genes with enhanced H4K12la after IL-17A stimulation were primarily related to cell cycle regulation (Fig. [165]6c). Next, we performed multi-omics analyses by combining data from lesional skin samples of psoriasis patients, ear skins from IMQ-treated mice, and H4K12la-targeted CUT&Tag-seq. Thirteen genes displayed elevated mRNA levels in psoriasis and enhanced H4K12la binding to their promoter regions after IL-17A stimulation (Fig. [166]6d). Among these genes, FOXM1, CCNB2 and CDC25C, which play crucial roles in cell cycle regulation, were identified (Fig. [167]6e). Increased expression of these three genes was observed in skin lesions from psoriasis patients (Fig. [168]6f) and mice (Fig. [169]6g and Supplementary Fig. [170]9c), as well as IL-17A-stimulated HaCaT cells (Supplementary Fig. [171]9d). Furthermore, the analysis of scRNA-seq data showed that the upregulation of FOXM1, CCNB2 and CDC25C was predominantly observed in keratinocytes (Supplementary Fig. [172]9e). Clinical trials also indicated a significant decrease in FOXM1, CCNB2 and CDC25C expression in patients treated with anti-IL-17RA antibody brodalumab (Supplementary Fig. [173]9f). Knockdown of KLK8 in HaCaT cells (Fig. [174]6h) and human primary keratinocytes (Fig. [175]6i), as well as knockdown of SLC16A1 (Supplementary Fig. [176]9g) or treatment with AZD3965 (Supplementary Fig. [177]9h) to inhibit H4K12la levels, significantly suppressed the IL-17A-induced increase in FOXM1, CCNB2 and CDC25C expression. This reduction was also observed in psoriatic mice applied with AAV-Krt14-shKlk8 or si-Klk8 (Fig. [178]6j and Supplementary Fig. [179]9i). Moreover, there was a significant correlation between KLK8 and these three genes, as well as between SLC16A1 and these three genes, observed in both normal and psoriatic individuals (Supplementary Fig. [180]9j, k). In contrast, the addition of lactate, which enhanced H4K12la levels, not only promoted the expression of FOXM1, CCNB2, and CDC25C in vitro and in vivo, but also blocked the inhibitory effect of anti-IL-17A antibodies on these three genes (Fig. [181]6k, l). Fig. 6. Keratinocytes-specific histone H4 lysine 12 lactylation regulates cell cycle-related genes. [182]Fig. 6 [183]Open in a new tab a H4K12la genomic loci was divided into unchanged peaks (cluster 1), up-regulated peaks (cluster 2) and down-regulated peaks (cluster 3) by the CUT&Tag assay after 50 ng/mL IL-17A stimulation. b Genome-wide distributions of upregulated H4K12la binding peaks (cluster 2). c Pathway enrichment of genes upregulated by H4K12la modification upon IL-17A induction by Metascape ([184]https://metascape.org/). d The Venn diagram represents the convergence of the human psoriasis database, the mouse psoriasis database, and genes that are upregulated in the CUT&Tag promoter regions. e Genome Browser tracking of CUT&Tag signals representing target gene loci. f Microarray analysis of FOXM1, CCNB2, and CDC25C mRNA in skin tissues of control subjects (n = 64) and psoriasis patients (n = 58). “NN” represents normal skin, “PN” represents psoriasis non-lesional skin, and “PP” represents psoriasis lesional skin. g The mRNA levels of Foxm1, Ccnb2, and Cdc25c in whole dorsal skin tissues of control or IMQ-induced psoriasis mice. n  = 8 mice per group. h, i The mRNA levels of FOXM1, CCNB2 and CDC25C in HaCaT cells (h) and human primary keratinocytes (i) stimulated with 50 ng/mL IL-17A for 24 h after KLK8 knockdown. n = 3 experiments. j The mRNA levels of Foxm1, Ccnb2 and Cdc25c in whole skin tissues from AAV-Krt14-sh-NC-treated and AAV-Krt14-sh-Klk8-treated psoriatic mice. n  = 5 mice per group. k HaCaT cells stimulated with 50 ng/mL IL-17A were treated with 10 μg/mL GR1501 for 24 h in the presence or absence of 10 mM sodium lactate. Cells were collected for the detection of FOXM1, CCNB2, and CDC25C expression by qPCR. n = 3 experiments. l The mRNA levels of Foxm1, Ccnb2, and Cdc25c in whole skin tissues from psoriatic mice, psoriatic mice treated with anti-mIL-17A antibody, and psoriatic mice injected with anti-mIL-17A antibody and Nala. n  = 9 mice per group. (m, n) Genome Browser tracking of CUT&Tag signals indicated KLK8 and IL17RA gene loci (m), and detected by qPCR (n). n = 3 experiments. Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001; ns, not significant. Statistical analysis was performed using a hypergeometric test (c), two-tailed unpaired Student’s t tests (g–l, and n), or one-way ANOVA (f). Source data are provided as a Source Data file. Furthermore, apart from cell cycle-related genes, significantly increased H4K12la peaks were observed in the promoter regions of multiple inflammatory factors and their receptors, including IL17RA (Fig. [185]6m and Supplementary Fig. [186]9l). The upregulation of IL-17RA expression was confirmed in IL-17A-stimulated keratinocytes (Supplementary Fig. [187]9m) and at the site of skin lesions in human psoriatic skin tissues (Supplementary Fig. [188]9n). In addition, in the promoter region of KLK8, we also found and verified a remarkable augmentation of H4K12la peak in the IL-17A group (Fig. [189]6m). Chromatin precipitation experiments demonstrated that knockdown of KLK8 resulted in reduced H4K12la binding within the promoter region (Fig. [190]6n). Considering the dependence of H4K12la on KLK8, the interaction between KLK8 and IL-17RA, as well as the promotion of IL17RA and KLK8 expression by H4K12la modification, there may exist a positive feedback loop involving IL-17RA, KLK8, and H4K12la. This feedback loop drives IL-17A-mediated accelerated keratinocyte division throughout the cell cycle, sustaining excessive keratinocyte proliferation and activation, and continuously impelling the progression of psoriasis. HAT1 functions as a “writer” to regulate H4K12la in psoriatic keratinocytes We used bioinformatics approaches to investigate several candidate acetyltransferases^[191]29, including EP300, KAT2A and KAT8, which have been proposed as “writers” of histone lactylation^[192]30–[193]32. Among these, only HAT1 was significantly up-regulated in skin tissues of both psoriasis patients and imiquimod-induced psoriasis mice (Fig. [194]7a and Supplementary Fig. [195]10a). Further analysis revealed that HAT1 exhibited higher expression levels in the skin compared to other acetyltransferases, primarily in the psoriatic keratinocytes (Supplementary Fig. [196]10b–g). Our results demonstrated a significant increase in the expression of both HAT1 mRNA (Fig. [197]7b) and protein (Fig. [198]7c) in dorsal skin tissue of imiquimod-induced psoriasis mice. Fig. 7. HAT1 regulates H4K12la in psoriatic keratinocytes. [199]Fig. 7 [200]Open in a new tab a Volcano plots demonstrating the differential expression of classical acetyltransferases in the skin tissues of psoriasis patients (left) and imiquimod-induced psoriasis mice (right) compared to normal controls. b, c The mRNA (b) and protein (c) levels of HAT1 in whole skin tissues of control mice and imiquimod-induced psoriasis mice. n  = 8 mice per group. d Molecular docking predicts the binding site of HAT1-H4 protein complex with lactyl-CoA. e HaCaT cells were stimulated with 50 ng/mL IL-17A for 24 h and harvested for immunoprecipitation and immunoblotting. n = 3 experiments. f HaCaT cells transfected with si-NC or si-HAT1 were stimulated with 50 ng/mL IL-17A for 24 h, and the locations of H4K12la (green) and HAT1 (red) were examined by laser confocal. n = 3 experiments. Scale bar: 20 μm. g The mRNA levels of HAT1 in HaCaT cells stimulated with 50 ng/mL IL-17A for 24 h. n = 3 experiments. h The expression of HAT1 in skin tissues of psoriasis patients (PsO) (n = 7) and brodalumab-treated psoriasis patients (Bro-T) (n = 7). i Dot plot of HAT1 expression in normal and lesional sites in psoriasis patients before and after treatment with anti-IL-17A monoclonal antibody secukinumab. j, k HaCaT cells (j) or human primary keratinocytes (k) were transfected with si-NC or si-HAT1, and then stimulated with 50 ng/mL IL-17A for detection of H4K12la expression. n = 3 experiments. l, m HaCaT cells were transfected with si-Ctrl or si-HAT1 and stimulated with 50 ng/mL IL-17A. l Cell viability. n = 3 experiments. m Migration ability. n = 3 experiments. Scale bar: 100 μm. n, o HaCaT cells (n) and human primary keratinocytes (o) were transfected with si-Ctrl or si-HAT1 and stimulated with 50 ng/mL IL-17A. The mRNA levels of FOXM1, CCNB2, CDC25C, and HAT1 were tested by qPCR. n = 3 experiments. Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001. Statistical analysis was performed using two-tailed paired (h) or two-tailed unpaired Student’s t tests (a–c, g, and l–o). Source data are provided as a Source Data file. While HAT1 is known to catalyze histone acetylation^[201]33–[202]35, there is currently no report suggesting its involvement in lactylation. Molecular docking analysis indicated that lactyl-coenzyme A can interact with lysine 12 of histone H4, involving glutamate at position 187 of HAT1 (Fig. [203]7d and Supplementary Fig. [204]11a). We next confirmed the interaction between HAT1 and H4K12la (Fig. [205]7e, f and Supplementary Fig. [206]11b). Furthermore, IL-17A greatly induced upregulation of HAT1 but not KAT2A, KAT8 and EP300 (Fig. [207]7g and Supplementary Fig. [208]11c). The HAT1 expression was significantly decreased after treatment with secukinumab and brodalumab in the clinic (Fig. [209]7h, i). Knockdown of HAT1 led to a remarkable reduction in IL-17A-induced H4K12la in human primary keratinocytes and HaCaT cells (Fig. [210]7j, k and Supplementary Fig. [211]11d, e), but not H4K12ac (Supplementary Fig. [212]11f). Next, we found that HAT1 expression was upregulated in FOXM1^+, CCNB2^+, and CDC25C^+ keratinocytes populations from psoriasis patients sc-RNA data (Supplementary Fig. [213]11g) compared to other histone acetyltransferases, and showed a significant correlation between FOXM1, CCNB2 and CDC25C in psoriasis patients skin tissues (Supplementary Fig. [214]11h). Moreover, the knockdown of HAT1 significantly inhibited IL-17A-induced proliferation and migration (Fig. [215]7l, m) and resulted in decreased expression of H4K12la-targeted genes FOXM1, CCNB2 and CDC25C both in HaCaT cells and human primary keratinocytes (Fig. [216]7n, o). In psoriasis mice, the binding of HAT1 to H4K12la in skin tissues was higher compared to control mice (Fig. [217]8a and Supplementary Fig. [218]11i). Similarly, the co-localization of HAT1 and H4K12la also showed an elevation in skin tissues of psoriasis patients (Fig. [219]8b), suggesting the specific role of HAT1 as a writer of H4K12la in keratinocytes. Moreover, we also silenced HAT1 in an imiquimod-induced psoriasis model. Treatment with si-Hat1 significantly attenuated the severity of psoriasis, as evidenced by diminished epidermal thickness and attenuated inflammation and tissue destruction (Fig. [220]8c–e and Supplementary Fig. [221]11j). Moreover, it led to a reduction in levels of lactate (Fig. [222]8f), H4K12la and KLK8 (Fig. [223]8g), as well as the expression of cell cycle genes regulated by H4K12la (Fig. [224]8h). Taken together, HAT1 expression and its ability to write lactylation into H4K12 is very important for keratinocyte hyperactivation in the pathogenesis of psoriasis. Fig. 8. Knockdown of HAT1 improves psoriasis-like symptoms in mice. [225]Fig. 8 [226]Open in a new tab a, b Immunofluorescence detection of H4K12la (green) and HAT1 (red) in skin tissues of imiquimod-induced psoriatic mice (a) or psoriasis patients (b). “Epi” stands for the epidermis and “dermis” for the dermis. Scale bar: 100 μm. n  = 5 per group. c–h Hydrogel containing negative control siRNA (si-Ctrl) or Hat1 siRNA (si-Hat1) was topically applied to the back of mice daily. The psoriasis model was then induced in these mice by applying imiquimod cream. c Skin tissues harvested from psoriatic mice on day 4 were analyzed by H&E. Scale bar: 100 μm. d The daily PASI score. e Skin thickness. f Lactate levels in whole skin tissues. g The protein levels of HAT1, KLK8, and H4K12la in whole skin tissues. h The mRNA levels of Hat1, Foxm1, Ccnb2, Cdc25c, Pcna, and Mki67 in whole skin tissues. n  = 5 mice per group. Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001. Statistical analysis was performed using two-tailed unpaired Student’s t tests (d–h). Source data are provided as a Source Data file. Targeting H4K12la inhibits keratinocyte hyperactivation and ameliorates psoriasis progression in mice Given the finding that IL-17A-induced H4K12la drives hyperactivation of keratinocytes, we sought to target this mechanism using rational pharmacological approaches. To this end, we focused on inhibiting lactate production by oxamate (an LDHA inhibitor) and 2-DG (a HK2 inhibitor). Treatment with oxamate or 2-DG significantly reduced IL-17A-induced H4K12la expression (Supplementary Fig. [227]12a, b) and effectively inhibited the proliferation and migration of IL-17A-stimulated HaCaT cells (Supplementary Fig. [228]12c–f). Furthermore, we examined the expression of genes regulated by H4K12la and found that both oxamate and 2-DG significantly reduced the expression of cell cycle-related genes, including FOXM1, CCNB2 and CDC25C (Fig. [229]9a, b). Fig. 9. Pharmacological inhibition of H4K12la inhibits psoriatic keratinocyte hyperproliferation and ameliorates psoriasis progression. [230]Fig. 9 [231]Open in a new tab a, b HaCaT cells were pretreated with 40 mM oxamate (a) or 10 mM 2-DG (b) for 2 h, followed by the stimulation of 50 ng/mL IL-17A for 24 h. The mRNA expressions of MKI67, PCNA, FOXM1, CCNB2, and CDC25C were tested by qPCR. n = 3 experiments. c–i Psoriasis model was induced in mice using imiquimod cream. Oxamate (0.5 g/kg) or 2-DG (0.5 g/kg) was given i.p. one day beforehand and then once a day. c Skin tissues harvested from psoriatic mice on day 4 were analyzed by H&E. Scale bar: 100 μm. d The daily PASI score. e Skin thickness. f Lactate levels in whole skin tissues. g H4K12la and PCNA expression in whole skin tissues. h The mRNA levels of inflammatory factors (Il17a, Il23a, Tnf and Il6) in whole skin tissues. i The mRNA levels of proliferation-related genes (Pcna, Mki67, Foxm1, Ccnb2, and Cdc25c) in whole skin tissues. n  = 5 mice per group. j–l Psoriasis model were induced in mice using imiquimod cream. 2-DG (0.3 g/kg) was given i.p. one day in advance and then once daily. The anti-mIL-17A antibody (30 μg/mice) was given s.c. the day before day 0 and again on day 2. j The daily PASI score. k Skin tissues harvested from psoriatic mice on day 5 were analyzed by H&E. Scale bar: 100 μm. l Skin thickness. n  = 7 mice per group. m Graphical abstract. Bars represent mean ± SD; p-values are indicated, *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001; ns, not significant. Statistical analysis was performed using two-tailed unpaired Student’s t tests (a, b, d–g, j, and l), or one-way ANOVA (h and i). Source data are provided as a Source Data file. In the imiquimod-induced mouse model of psoriasis, treatment with oxamate and 2-DG exhibited significant therapeutic effects, including reduced skin inflammation, PASI score, skin epidermal layer thickness, and lactate content in skin tissues (Fig. [232]9c–f). Treatment with these inhibitors also downregulated H4K12la expression and inhibited PCNA expression associated with cell proliferation (Fig. [233]9g). In addition, they inhibited the expression of inflammation- (Il17a, Il23a, Tnf and Il6) and proliferation-related (Pcna, Mki67, Foxm1, Ccnb2, and Cdc25c) genes (Fig. [234]9h, i). Furthermore, oxamate and 2-DG treatment led to a significant reduction in the expression of Hat1 (Supplementary Fig. [235]12g) and Slc16a1 (Supplementary Fig. [236]12h). Tissue immunofluorescence analysis demonstrated that drug treatment suppressed the expression and co-localization of H4K12la and HAT1 (Supplementary Fig. [237]12i). Co-administration of anti-mIL-17A antibody (30 μg/mouse) and 2-DG (0.3 g/kg) effectively suppressed psoriasis development, showing stronger efficacy in reducing PASI score, skin thickening, and H4K12la expression than either treatment alone (Fig. [238]9j–l and Supplementary Fig. [239]12j). These results suggest that targeting IL-17A-induced H4K12la in keratinocytes could be a promising strategy for alleviating psoriasis (Fig. [240]9m). Discussion IL-17 signaling is known to be deeply involved in the pathogenesis of various autoimmune diseases. However, the exact role of IL-17 signaling in the different manifestations of different diseases remains unknown. In this study, we focused on unraveling the detailed mechanism of IL-17A signaling in the pathogenesis of psoriasis. Our results identified KLK8 as a keratinocyte-specific protein that mediated IL-17A-driven keratinocyte hyperactivation, independently of IL-17A-induced canonical chemokine production. This non-canonical IL-17A signaling pathway involved IL-17RA/KLK8 interaction, lactate production, H4K12la catalyzed by HAT1, and subsequent upregulation of cell cycle gene expressions. We provide insights into the distinction between IL-17A-induced pro-inflammatory factor production and keratinocyte hyperproliferation in psoriasis, highlighting the role of KLK8-mediated regulation of IL-17A signaling on keratinocyte hyperproliferation. We further characterized H4K12la as a key mechanism of the non-canonical IL-17A signaling pathway, contributing to the main pathology of psoriasis by inducing the upregulation of various cell cycle-related genes (e.g., FOXM1, CCNB2, and CDC25C), resulting in accelerated proliferation of psoriatic keratinocytes. In addition, H4K12la was found to increase the expression of both KLK8 and IL-17RA in IL-17A-stimulated keratinocytes. Thus, our study uncovers the existence of a positive feedback loop in non-canonical IL-17A signaling that drives psoriasis progression through IL-17RA/KLK8/H4K12la/cell cycle genes. Histone lactylation is a tightly regulated process, yet the specific “writers” responsible for distinct lysine modifications and their molecular mechanisms remain largely uncharacterized. We found that only H4K12la was significantly upregulated in skin epidermal keratinocytes from imiquimod-induced psoriatic mice and IL-17A-stimulated HaCaT cells. This selective induction of H4K12la by IL-17A may involve multiple interrelated factors. First, IL-17A selectively upregulated HAT1 but not EP300 or KAT2A (reported to be associated with H3K18 modifications^[241]31,[242]36), implying that enzyme availability could dictate site specificity. Prior studies indicate that acyltransferases form distinct complexes which exhibit substrate preferences for