Honokiol, an inducer of sirtuin‐3, protects against non‐steroidal anti‐inflammatory drug‐induced gastric mucosal mitochondrial pathology, apoptosis and inflammatory tissue injury

Background and Purpose Mitochondrial oxidative stress, inflammation and apoptosis primarily underlie gastric mucosal injury caused by the widely used non‐steroidal anti‐inflammatory drugs (NSAIDs). Alternative gastroprotective strategies are therefore needed. Sirtuin‐3 pivotally maintains mitochondrial structural integrity and metabolism while preventing oxidative stress; however, its relevance to gastric injury was never explored. Here, we have investigated whether and how sirtuin‐3 stimulation by the phytochemical, honokiol, could rescue NSAID‐induced gastric injury. Experimental Approach Gastric injury in rats induced by indomethacin was used to assess the effects of honokiol. Next‐generation sequencing‐based transcriptomics followed by functional validation identified the gastroprotective function of sirtuin‐3. Flow cytometry, immunoblotting, qRT‐PCR and immunohistochemistry were used measure effects on oxidative stress, mitochondrial dynamics, electron transport chain function, and markers of inflammation and apoptosis. Sirtuin‐3 deacetylase activity was also estimated and gastric luminal pH was measured. Key Results Indomethacin down‐regulated sirtuin‐3 to induce oxidative stress, mitochondrial hyperacetylation, 8‐oxoguanine DNA glycosylase 1 depletion, mitochondrial DNA damage, respiratory chain defect and mitochondrial fragmentation leading to severe mucosal injury. Indomethacin dose‐dependently inhibited sirtuin‐3 deacetylase activity. Honokiol prevented mitochondrial oxidative damage and inflammatory tissue injury by attenuating indomethacin‐induced depletion of both sirtuin‐3 and its transcriptional regulators PGC1α and ERRα. Honokiol also accelerated gastric wound healing but did not alter gastric acid secretion, unlike lansoprazole. Conclusions and Implications Sirtuin‐3 stimulation by honokiol prevented and reversed NSAID‐induced gastric injury through maintaining mitochondrial integrity. Honokiol did not affect gastric acid secretion. Sirtuin‐3 stimulation by honokiol may be utilized as a mitochondria‐based, acid‐independent novel gastroprotective strategy against NSAIDs.