Aloperine induces methuosis in non-small cell lung cancer by targeting VPS34 lactylation and disrupting the Armus/Rab7 axis

Non-small cell lung cancer (NSCLC) represents the most prevalent form of malignant tumor and constitutes a principal cause of cancer-related mortality globally. Conventional therapeutic approaches predominantly induce apoptosis; however, their efficacy is often compromised by the development of drug resistance. Methuosis, a form of regulated cell death distinct from apoptosis, is characterized by aberrant macropinocytosis and the formation of cytoplasmic vacuoles. Aloperine (ALO), a naturally occurring antitumor alkaloid, has been observed to induce methuosis in cancer cells, although its precise molecular targets and mechanisms remain to be elucidated. This study investigated the anti-NSCLC effects of ALO using cell lines, patient-derived organoids, and mouse xenograft models. Through various assays, it was demonstrated that ALO directly interacts with VPS34 at the I760 residue and promotes TIP60-mediated lactylation of VPS34 at K356 and K781. This interaction inhibits VPS34 kinase activity and reduces intracellular PI(3)P production. The subsequent decrease in PI(3)P levels impedes Armus endosomal recruitment, disrupts Rab7 cycling, leads to the accumulation of macropinosomes, and impairs endolysosomal fusion, ultimately inducing methuosis. ALO exhibits significant antitumor efficacy and acts synergistically with cisplatin to co-activate methuosis and apoptosis, all while avoiding noticeable systemic toxicity. Collectively, ALO targets VPS34 lactylation and disrupts Armus/Rab7 signaling. When used in conjunction with cisplatin, it constitutes a safe and effective therapeutic strategy for NSCLC.