Imeglimin halts cyclophosphamide-induced ovarian injury: a dual modulation of TLR4/NF-κB/NLRP3-driven inflammation and AMPK/SIRT1/PGC-1α pathways.

Cyclophosphamide (CPA) induces premature ovarian insufficiency (POI) through oxidative stress, inflammation, pyroptosis, and apoptosis, posing a significant fertility risk in cancer survivors; this study investigates imeglimin's protective effects against CPA-induced POI in female rats by modulating TXNIP-NLRP3 inflammasome activation and AMPK/SIRT1/PGC-1α signaling. Female rats were divided into four groups: control, imeglimin (IMEG) alone, CPA, and CPA + IMEG. Body/ovarian weights and estrous cycles were monitored, with serum estradiol, FSH, and AMH measured by ELISA. Oxidative stress (MDA, GSH, CAT), inflammation (TNF-α, IL-18, IL-1β by ELISA; NF-κB by IHC), apoptosis (cleaved caspase-3), and signaling pathways (TXNIP, NLRP3, caspase-1, p-AMPK, SIRT1, PGC-1α by Western blot; TLR4, MYD88, ASC, GSDMD, Bax, Bcl-2 by qRT-PCR) were assessed. CPA significantly reduced body/ovarian weights, disrupted estrous cycles, lowered estradiol/AMH while elevating FSH, increased MDA but decreased GSH/CAT, upregulated NF-κB/TNF-α/IL-18/IL-1β/cleaved caspase-3, and enhanced TXNIP/NLRP3/caspase-1/TLR4/MYD88/ASC/GSDMD/Bax while suppressing Bcl-2, resulting in a significantly higher Bax/Bcl-2 ratio, p-AMPK/SIRT1/PGC-1α. IMEG co-treatment reversed these changes, restoring weights/cycles/hormones, attenuating oxidative/inflammatory/apoptotic markers, inhibiting NLRP3 inflammasome/pyroptosis pathways, and activating p-AMPK/SIRT1/PGC-1α signaling. Imeglimin attenuates CPA-induced premature ovarian insufficiency via inhibition of oxidative, inflammatory, and pyroptotic damage and p-AMPK/SIRT1/PGC-1α activation, as evidenced by preservation of ovarian structural integrity, follicular architecture, and endocrine markers. These findings highlight its potential as a candidate for chemotherapy-associated ovarian protection, pending further validation through direct fertility outcome studies.