Ultraviolet B-induced oxidative stress drives stromal remodeling and malignant transformation of actinic keratosis via a podoplanin-C-type lectin-like receptor 2 signaling axis.

Ultraviolet B (UVB) radiation induces oxidative stress and promotes photocarcinogenesis; however, the molecular mechanisms linking oxidative stress to the malignant transformation of actinic keratosis (AK) remain incompletely understood. Here, we performed an integrative multi-omics analysis of six independent cohorts combining bulk RNA sequencing, single-cell transcriptomics, functional experiments, and clinical validation. UVB irradiation induced oxidative stress and significantly increased podoplanin (PDPN) expression in keratinocytes in a dose-dependent manner. Mechanistically, keratinocyte-derived PDPN interacted with C-type lectin-like receptor 2 (CLEC-2) on fibroblasts through its platelet aggregation-stimulating (PLAG) domain, triggering fibroblast senescence and the senescence-associated secretory phenotype (SASP), characterized by enhanced secretion of matrix metalloproteinase-1 (MMP-1) and interleukin-6 (IL-6). Single-cell transcriptomic analysis identified 272 epithelial-specific hub genes converging on PDPN-centered regulatory networks, and a 12-gene signature demonstrated strong diagnostic performance and prognostic value. Functional studies showed that PDPN silencing markedly attenuated UVB-induced cell migration and SASP activation, whereas deletion of the PLAG domain abolished PDPN-CLEC-2 interaction. Analysis of human specimens further demonstrated progressive upregulation of PDPN and CLEC-2 expression during the transition from normal skin to AK and cutaneous squamous cell carcinoma (cSCC). Collectively, our findings identify a PDPN-CLEC-2-mediated stromal remodeling program that links UVB-induced oxidative stress to malignant transformation in AK and highlight this signaling axis as a potential therapeutic target for photochemoprevention.