Downregulating CHI3L2 via the STAT3 Pathway: The Mechanism of Calcitriol in Suppressing Psoriatic Inflammation and Keratinocyte Hyperproliferation.

Psoriasis is a chronic inflammatory skin disorder driven by immune dysregulation and keratinocyte hyperproliferation. Calcitriol, the active form of vitamin D, shows therapeutic potential, but its molecular mechanisms remain incompletely understood. CHI3L2 (chitinase-3-like protein 2) is a member of the chitinase-like protein family implicated in inflammatory and tissue-remodelling processes, yet its role in psoriasis has not been explored. Here, we investigated whether CHI3L2 mediates the anti-psoriatic effects of calcitriol. Topical application of calcitriol alleviated imiquimod (IMQ)-induced psoriasiform lesions in both unilateral and bilateral mouse ear models, as evidenced by reduced clinical scores, epidermal thickening and pro-inflammatory cytokine expression (IL-1α, IL-6, IL-17A, IL-23A). In M5-stimulated HaCaT cells, calcitriol reversed aberrant proliferation, migration and inflammatory responses, and restored keratin expression (KRT1/KRT6). RNA-seq identified CHI3L2 as the most significantly downregulated gene following calcitriol treatment. CHI3L2 knockdown phenocopied the protective effects of calcitriol, suppressing cell proliferation, migration and inflammation. Mechanistically, calcitriol downregulated CHI3L2 via inhibition of STAT3 phosphorylation at Tyr705. Collectively, these findings demonstrate that calcitriol ameliorates psoriatic inflammation and keratinocyte hyperproliferation through CHI3L2 downregulation mediated by the STAT3 pathway, highlighting CHI3L2 as a potential therapeutic target for psoriasis.