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ACTR3 (actin\u2010associated 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\u2010hydroxyisobutyrylation (Khib)\u2014a critical post\u2010translational modification\u2014exerts 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\u2010modified 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)\u2010induced psoriatic mice. Further validation using ACTR3 K42A mutation experiments confirmed that decreased Khib modification at this site exacerbates IMQ\u2010induced 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\u2010Khib modification of ACTR3 enhances keratinocyte proliferation by activating the TAK1\u2010MK2\u2010HSP27 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\u2010MK2\u2010HSP27 signalling pathway, offering a previously undescribed molecular insight into psoriasis pathogenesis.<\/jats:p>","DOI":"10.1111\/febs.70558","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T11:21:23Z","timestamp":1778066483000},"page":"6114-6136","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ACTR3<\/scp>\n                    enhances the hyperproliferation of psoriatic keratinocytes by activating the\n                    <scp>TAK1<\/scp>\n                    \u2010\n                    <scp>MK2<\/scp>\n                    \u2010\n                    <scp>HSP27<\/scp>\n                    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