目的:目前的证据表明,由于各种不良反应,没有完全有效的子宫内膜异位症(EMS)方法而没有创伤。可靠的证据表明,抑制铁死亡是EMS的潜在策略。我们充分证实内源性蛋白PDZ和LIM结构域3(PDLIM3)在EMS中的表达显著增加。
方法:PDLIM3敲低降低了原发性异位子宫内膜基质细胞(EESCs)的活力和迁移,和升高的铁凋亡信号指标,包括Fe2+,丙二醛(MDA),EESCs中的活性氧(ROS)。
结果:机制研究表明,抑制PDLIM3加速了神经胶质瘤相关癌基因-1(Gli1)的降解,并进一步使Hedgehog信号失活。Gli1抑制剂,GANT61,消除了PDLIM3缺失对EESC生长的影响,迁移,和铁中毒。体内实验表明,PDLIM3的减少抑制了子宫内膜病变的生长。同样,抑制PDLIM3可促进子宫内膜病变中的铁凋亡并减弱Hedgehog信号传导。
结论:总的来说,PDLIM3的沉默通过诱导Gli1降解和阻断Hedgehog信号传导促进EMS中的铁凋亡。它可能为将来开发EMS的治疗剂提供替代策略。
OBJECTIVE: Current evidence suggests that there is no completely effective method for endometriosis (EMS) without trauma due to diverse adverse effects. Reliable evidence illustrates that inhibiting ferroptosis is a potential strategy for EMS. We sufficiently verified that the expression of endogenous protein PDZ and LIM domain 3 (PDLIM3) was significantly increased in EMS.
METHODS: PDLIM3 knockdown reduced primary ectopic endometrial stromal cells\' (EESCs) viability and migration, and elevated ferroptosis signaling indicators including Fe2+, malondialdehyde (MDA), and reactive oxygen species (ROS) in EESCs.
RESULTS: Mechanistic studies revealed that inhibition of PDLIM3 accelerated glioma-associated oncogene-1 (Gli1) degradation and further deactivated Hedgehog signaling. Gli1 inhibitor, GANT61, abrogated the impact of PDLIM3 deletion on EESC growth, migration, and ferroptosis. In vivo experiments suggested that PDLIM3 reduction repressed the growth of endometrial lesions. Likewise, repression of PDLIM3 promoted ferroptosis and attenuated Hedgehog signaling in endometrial lesions.
CONCLUSIONS: Collectively, silencing of PDLIM3 facilitates ferroptosis in EMS by inducing Gli1 degradation and blocking Hedgehog signaling. It may provide an alternative strategy for developing therapeutic agents of EMS in the future.