Andrographolide blocked the progression of endometriosis by promoting ferroptosis via inhibiting anabolism of serine.

Ferroptosis is a potential target for the treatment of endometriosis (EMs). The role of andrographolide (AP) in the ferroptosis has gradually attracted attention, but its mechanism of action in endometriosis has not been clarified. Here we investigated the inhibitory effect of AP on endometriosis and its mechanism. Our results showed that AP treatment inhibited progression of ectopic endometrial 12Z cells. We also demonstrated that AP treatment induced ferroptosis and apoptosis in 12Z cells. Combined metabolomics and transcriptomic analysis indicated that AP might exert its effect by down-regulating PSAT1 and PHGDH to inhibit serine synthesis. Knockdown of PSAT1 expression elevated ferroptosis level and blocked progression of 12Z cells; however, the ferroptosis inhibitor Ferrostatin-1 (Fer-1), phosphoserine, or serine mitigated these phenotypes. We also observed that AP inhibited the EMs progression and either PSAT1 or PHGDH level in mice model. Finally, AP exhibited inhibitory effects on the viability of ectopic endometrial stromal cells (EESCs) and the expression of PSAT1, as well as induced ferroptosis in EESCs. Overall, AP is a new potential drug for the treatment of endometriosis.