2. Academic Validation
  3. Keratinocyte-specific H4K12 lactylation drives a non-canonical IL-17-dependent signaling in psoriasis progression in mice

Keratinocyte-specific H4K12 lactylation drives a non-canonical IL-17-dependent signaling in psoriasis progression in mice

  • Nat Commun. 2025 Sep 30;16(1):8639. doi: 10.1038/s41467-025-63791-7.
Xuecheng Shen # 1,  Wenxuan Qiao # 1,  Wei Yan 2,  Hao Xie 3,  Chenyang Zhang 1,  Yang Sun 1,  Qiong Luo 4,  Qiang Xu 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, China.
  • 2 Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, China.
  • 3 School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, China. qiongluo@nju.edu.cn.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, China. molpharm@163.com.
  • 6 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China. molpharm@163.com.
  • # Contributed equally.
PMID: 41027887 DOI: 10.1038/s41467-025-63791-7
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.

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