mTOR blockade mitigates chemotherapy drug-induced intestinal toxicity via inhibition of pyroptosis.

Mammalian target of rapamycin (mTOR) signaling constitutes a crucial intracellular signaling pathway indispensable for regulating a variety of pathophysiological processes, including cancers. Intriguingly, the inhibition of mTOR can reverse the adverse effects induced by chemotherapy drugs; however, the fundamental mechanism underlying this phenomenon remains unclear. In this study, we demonstrate that mTOR signaling blockade can mitigate etoposide- or cisplatin-induced intestinal injury in mice. The mTOR inhibitor AZD8055 can inhibit chemotherapy drug-induced normal cell pyroptosis, as manifested by a decreased proportion of PI-positive cells, attenuated intestinal cell swelling, and reduced release of lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1). We further determined that mTOR inhibition suppressed the cleavage of caspase-3 and gasdermin E (GSDME), suggesting the inhibition of the caspase3/GSDME signaling pathway. We also discovered that AZD8055 can impede chemotherapy drug-induced alterations in mitochondrial membrane potential, reactive oxygen species generation, and DNA damage in intestinal cells, which are the key upstream events for activating caspase-3. Correspondingly, data from in vivo mouse models also demonstrated that AZD8055 effectively curtailed intestinal DNA damage and inflammation induced by chemotherapy drugs. Importantly, although AZD8055 counteracts the side effects of chemotherapy drugs, it does not substantially affect their anti-tumor activity. Our study proposes the potential application of mTOR inhibitors as chemoprotective agents, presenting a means to prolong the duration of chemotherapy drug use and optimize the chemotherapeutic regimen.