Role and mechanism of lncRNA ZEB1-AS1 endogenous competition for miR-365a-3p targeting NRF2 in ferroptosis in articular chondrocytes.

Osteoarthritis (OA) is an extremely complex chronic whole joint disease. The regulation of NRF2 in cellular ferroptosis is involved in OA development; however, its upstream regulatory mechanism is unclear. Long noncoding RNAs (lncRNAs) regulate the expression of downstream target genes through endogenous competition with micro RNAs. LncRNA ZEB1-AS1 regulates the expression of miR-365a-3p, which in turn negatively regulates NRF2 expression. Both lncRNA ZEB1-AS1 and NRF2 can bind to miR-365a-3p at the same target site. However, it remains unclear whether ZEB1-AS1 could act as a competing endogenous RNA (ceRNA) to reduce miR-365a-3p-mediated inhibition of NRF2. Specifically, the potential mechanism whereby ZEB1-AS1 might sequester miR-365a-3p through competitive binding, thereby alleviating its suppressive effect on NRF2 expression, requires further experimental validation. Therefore, our study aimed to investigate whether lncRNA ZEB1-AS1 could participate in the regulation of NRF2 expression through endogenous competition for binding to miR-365a-3p, as well as the role and mechanism in osteoarthritic cellular ferroptosis. Our findings demonstrated that NRF2 knockdown combined with miR-365a-3p overexpression significantly enhanced cellular ferroptosis and accelerated osteoarthritis progression. Conversely, both miR-365a-3p inhibition and ZEB1-AS1 overexpression were found to upregulate NRF2 expression, thereby mitigating cellular ferroptosis and OA development. Notably, ZEB1-AS1 overexpression exerted dual protective effects in chondrocytes by elevating NRF2 levels, effectively suppressing both ferroptosis and inflammatory damage. Mechanistically, we identified that the lncRNA ZEB1-AS1 modulates OA pathogenesis through the miR-365a-3p/NRF2 axis, suggesting this pathway may serve as a potential therapeutic target for early intervention in OA progression.