Enhancing platinum-based chemotherapy efficacy and safety through combination therapy-mediated remodeling of autophagic homeostasis in gastric cancer

Platinum-based drugs exhibit potent anti-tumor efficacy but are limited by low bioavailability, severe toxicity, and resistance. Current therapeutic strategies lack effective solutions due to the unclear molecular mechanisms. Autophagy, with its dual protective/destructive roles, offers potential to enhance platinum-based chemotherapy, yet its clinical translation for optimizing therapeutic outcomes remains underexplored. To address this challenge, we screened a Natural Compounds Library (NCL) to identify low-toxicity agents that synergize with Cisplatin (Cis). Among 285 autophagy-related candidates, Catharanthine (CA) emerged as a specific autophagy activator model molecule that reduced toxicity and synergistically suppressed gastric cancer (GC) when combined with Cis. Mechanistically, CA promoted organ protection via endoplasmic reticulum stress (ERS)/AMPKα-dependent autophagy activation. The CA-Cis combination induced tumor-suppressive effects, including ERS, autophagosome accumulation, and cytoskeletal impairment in cancer cells. Conversely, CA-mediated autophagy protected normal cells, as AMPKα knockdown abolished this protection, resulting in DNA damage and apoptosis. These results highlight the dual autophagic flux regulation: tumor cells undergo destructive autophagy, while normal cells experience protective autophagy, establishing a favorable therapeutic balance. We confirmed that the CA-Cis combination activates autophagy through the AMPKα-ULK1 pathway in both tumor and non-tumor tissues and differentially regulates phosphorylation at serine 757 of ULK1, this differentiation can dramatically modulate autophagy activity, thereby mediating context-dependent dual outcomes of autophagic protection and detrimental effects. These findings elucidate a mechanism whereby CA enhances platinum efficacy by remodeling of autophagic homeostasis in organisms, providing a theoretical basis for optimizing platinum-based regimens. Our study bridges autophagy's dual functionality with clinical strategy, proposing the combination of specific autophagy activators as a promising approach to overcome platinum resistance and toxicity in GC treatment.