Sirtuin 3 is a common target of non-steroidal anti-inflammatory drugs to induce gastric cancer cell death and gastric mucosal injury.

Nonsteroidal anti-inflammatory drugs (NSAIDs), the quintessential medicines to treat pain and inflammatory conditions, induce cell death in human cancer cells, as repurposed anticancer agents, and in normal gastric mucosa, as a major side effect. The subcellular target/s of NSAIDs that leads to the cell death remained elusive so far. Here, by venturing transcriptomics followed by functional validation, we, for the first time, identified mitochondrial deacetylase Sirtuin 3 (Sirt3) as a non-canonical target of NSAIDs whose depletion induced the hyperacetylation of mitochondrial proteome, OGG1 depletion, mtDNA damage, electron transport chain defect associated mitochondrial dysfunction and finally cell death. Silencing of Sirt3 in AGS cells (a human gastric adenocarcinoma cell line) significantly aggravated NSAID-induced cytopathology. Whereas, honokiol mediated induction of Sirt3 corrected the NSAID-induced transcriptome alteration and gastropathy in rodent model. Together, the results identify Sirt3 as a common target used by NSAIDs to induce gastric carcinoma cell death and gastric mucosal injury. Gastric mucosal injury was developed by oral administration of typical NSAIDs including indomethacin (48 mg/kg), ibuprofen (400 mg/kg), diclofenac (75 mg/kg), aspirin (400 mg/kg) as required. Gastric injury was allowed to develop and after 4 hrs, the rats were subjected to terminal euthanasia followed by sacrifice and collection of mucosal tissue samples for transcriptome analysis and subsequent experiments. For HKL induced protection, rats were pre-treated with HKL (40 mg/kg), intraperitoneally, followed by oral administration of indomethacin after 30 minutes.