Diacerein alleviates endometrial fibrosis in an intrauterine adhesion model via ferroptosis inhibition.

Abstract

Intrauterine adhesion (IUA) is a significant contributor to uterine infertility, primarily characterized by endometrial fibrosis. Although diacerein exhibits anti-inflammatory and anti-fibrotic properties, its therapeutic potential in IUA remains unclear. This study investigated the protective effects of diacerein in an IUA rat model induced by mechanical injury. Histological analysis revealed that diacerein treatment alleviated endometrial damage, and immunohistochemical staining confirmed the restoration of CK19 and CK18 expression, indicating improved epithelial integrity and regeneration. Diacerein mitigated endometrial fibrosis by inhibiting epithelial-mesenchymal transition (EMT), as evidenced by increased E-cadherin and decreased N-cadherin expression, likely via suppression of TGFβ/SMAD2 signaling. Diacerein exerted anti-inflammatory effects in IUA rats. Notably, diacerein inhibited ferroptosis by reducing lipid peroxidation, limiting Fe²⁺ accumulation, and modulating ferroptosis-related proteins, including ACSL4, SLC7A11, GPX4, and FTH1. The protective effects of diacerein were mirrored by ferroptosis inhibitor Ferrostatin-1 treatment but reversed by ferroptosis inducer Erastin, confirming that diacerein alleviates endometrial fibrosis in IUA rats through ferroptosis suppression. Mechanistically, diacerein modulated the NRF2/HMGB1 signaling pathway, restoring NRF2 and HO1 levels while downregulating HMGB1 expression. Collectively, these findings suggest that diacerein effectively attenuates ferroptosis-mediated fibrosis in IUA, highlighting ferroptosis inhibition as a promising therapeutic strategy for IUA management.