ACTR3 enhances the hyperproliferation of psoriatic keratinocytes by activating the TAK1 ‐ MK2 ‐ HSP27 pathway

Psoriasis is a chronic immune-mediated skin disorder characterised by abnormal keratinocyte proliferation and cutaneous inflammation. ACTR3 (actin-associated protein 3) is significantly overexpressed in both cutaneous malignant tumours and psoriatic keratinocytes, and is recognised as a potential key nodal molecule linking tumours to inflammatory skin conditions. Lysine 2-hydroxyisobutyrylation (Khib)-a critical post-translational modification-exerts regulatory effects on the pathogenesis of various diseases; however, its specific role in psoriasis pathogenesis remains elusive. In this study, we demonstrated that elevated ACTR3 expression in cutaneous tumours and psoriasis promotes abnormal keratinocyte proliferation in psoriasis. Khib-modified protein profiles in epidermal tissues from psoriatic patients and healthy controls were analysed, leading to the identification of ACTR3 as a differential target protein. Results showed that Khib modification levels at the K42 site of ACTR3 were significantly reduced in lesional tissues from psoriatic patients and imiquimod (IMQ)-induced psoriatic mice. Further validation using ACTR3 K42A mutation experiments confirmed that decreased Khib modification at this site exacerbates IMQ-induced psoriatic inflammation and keratinocyte proliferation. Deacetylases Sirt1 and HDAC1 were found to reduce ACTR3 Khib modification levels, thereby regulating ACTR3 expression and subsequent keratinocyte (KC) proliferation. Additionally, signalling pathway analysis revealed that downregulated K42-Khib modification of ACTR3 enhances keratinocyte proliferation by activating the TAK1-MK2-HSP27 pathway. Notably, TAK1 antagonists effectively reversed abnormal keratinocyte proliferation and psoriatic inflammation induced by the ACTR3 K42A mutation. This study elucidates that reduced Khib modification at the ACTR3 K42 locus promotes keratinocyte proliferation via regulation of the TAK1-MK2-HSP27 signalling pathway, offering a previously undescribed molecular insight into psoriasis pathogenesis.