CircLDLR silencing alleviates the damage of keratinocytes induced by M5 cytokine via the miR-1294/TPX2 axis.

The hyperproliferation and aberrant inflammatory activation of epidermal keratinocytes constitute the core pathological features of psoriasis. While non-coding RNAs have emerged as critical epigenetic regulators, their specific contributions to psoriatic pathogenesis remain incompletely understood. In this study, we investigated the pathological significance of a novel circular RNA, circLDLR, which was identified via high-throughput sequencing and validated to be significantly upregulated in clinical psoriatic lesional tissues compared to normal skin. In vitro, utilizing an M5 cytokine-induced HaCaT keratinocyte model to mimic the psoriatic inflammatory microenvironment, we observed a concordant upregulation of circLDLR. Functional evaluations revealed that the targeted knockdown of circLDLR effectively mitigated M5-induced cellular hyperproliferation, pathological migration, and the excessive secretion of pro-inflammatory cytokines (IL-6, IL-1β, and IL-8). Mechanistically, RNA immunoprecipitation and dual-luciferase reporter assays elucidated that cytoplasmic circLDLR functions as a competing endogenous RNA (ceRNA) by physically sponging miR-1294, thereby de-repressing the expression of its downstream target, TPX2. Crucially, the phenotypic protection conferred by circLDLR silencing was significantly reversed by either miR-1294 inhibition or TPX2 overexpression. Collectively, our findings identify the circLDLR/miR-1294/TPX2 axis as a novel molecular driver of keratinocyte dysfunction, providing valuable histopathological insights and highlighting a promising therapeutic target for psoriasis.