Ramulus Mori alkaloids (SZ-A) sensitize triple-negative breast cancer to cisplatin via PLA2G2A-mediated ceramide metabolism

Abstract

Cisplatin (DDP) remains a standard therapy for triple-negative breast cancer (TNBC), yet intrinsic or acquired resistance often limits its efficacy; here, we report that Ramulus Mori alkaloids (SZ-A), an approved botanical α-glucosidase inhibitors, synergize with DDP to suppress TNBC progression in vitro and in vivo by driving PLA2G2A-dependent ceramide accumulation. Combining SZ-A with DDP synergistically inhibits viability, clonogenicity, migration, and invasion, induces S-phase arrest and apoptosis, and attenuates tumor growth in xenograft models. Mechanistically, SZ-A directly binds to and stabilizes PLA2G2A, blocking its autophagic-lysosomal degradation, leading to accumulated PLA2G2A that suppresses fatty acid oxidation and triggers ceramide accrual via ADIPOR2 inhibition. Genetic ablation of PLA2G2A abrogates these effects. DDP further enhances SZ-A-induced PLA2G2A upregulation and ceramide accumulation, resulting amplified cytotoxicity. Our findings reveal SZ-A as a chemosensitizing agent that enhances the efficacy of DDP in TNBC.

Keywords

Ramulus Mori alkaloids / Triple-negative breast cancer (TNBC) / Cisplatin / Phospholipase A2 Group IIA (PLA2G2A) / Ceramide

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82270879 and 82504844), the Foundation of Excellent Youth Scholars of Education Committee of Anhui Province of China (No. 2022AH030124), the Key Project of Natural Science Foundation of the Department of Education of Anhui Province (No. 2025AHGXZK31285).

Declaration of interest statement

These authors have no conflict of interest to declare.

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