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SCM-198 Prevents Endometriosis By Reversing Low Autophagy Levels Of Endometriotic Stromal Cells Via Inhibiting TNF-Α-Aromatase-Estrogen-Erα Pathway And Promoting PR Expression


 Background: Endometriosis (EMS), an estrogen-dependent disease, is characterized by dysregulated inflammation and increased estrogen in ectopic lesions. However, the crosstalk and pathogenic mechanism of inflammation and estrogen has not been fully explored. SCM-198 is the synthetic form of leonurine with multiple pharmacological activities. Whether SCM-198 could inhibit the progress of EMS by regulating inflammation and estrogen signaling remains unknown. Methods: The therapeutic effects and potential mechanisms of SCM-198 on EMS were analyzed by establishing EMS mice models and performing RNA-seq assay. ELISA was performed to detect estrogen and TNF-α concentration in normal endometrial stromal cells (nESCs) and ectopic endometrial stromal cells (eESCs), with or without SCM-198 treatment. Western blotting, RNA silencing and plasmid overexpression were utilized to analyze the relationship among inflammation, endocrine and autophagy as well as the regulation of SCM-198 on inflammation-endocrine-autophagy axis. Results: Increased estrogen-ERα signaling and decreased PR expression co-led to the hypo-autophagy state in eESCs, which further inhibited the apoptosis of eESCs. Highly expressed TNF-α in eESCs enhanced low-autophagy mediated anti-apoptosis effect by activating aromatase-estrogen-ERα signaling. SCM-198 inhibited the growth of ectopic lesions in EMS mouse model and promoted the apoptosis of eESCs both in vivo and in vitro. The apoptosis effect of SCM-198 on eESCs were realized by upregulating the autophagy level via inhibiting TNF-α activated aromatase-estrogen-ERα signaling and increasing PR expression. Conclusion: Inflammation facilitated the progress of EMS by disturbing estrogen regulatory axis. SCM-198 restrained the growth of EMS by regulating inflammation-endocrine-autophagy axis.