Resveratrol pretreatment in mouse heatstroke models and AML12 hepatocyte heat-exposure assays significantly reduced temperature dysregulation, liver morphological damage, lipid deposition, and necroptosis by directly binding to and suppressing Heat Shock Factor 1 (HSF1). Pharmacological HSF1 activation with agonist HSF1A replicated heat-induced liver injury, while HSF1 inhibition via KRIBB11 or genetic knockout mirrored resveratrol's protection — confirming HSF1 as the mechanistic linchpin. Importantly, necroptosis inhibition did not reverse lipid metabolic disorders, placing lipid dysregulation upstream of cell death signaling in this pathway.
This finding reframes resveratrol's well-documented pleiotropic benefits — typically attributed to SIRT1 activation or NF-κB suppression — around a HSF1-inhibition axis that is highly relevant to heat pathophysiology. HSF1 is canonically viewed as cytoprotective through heat shock protein induction, making its role here as a hepatotoxic driver a genuinely counterintuitive insight that could shift how acute heat illness is managed pharmacologically. The KRIBB11 comparison effectively separates resveratrol's HSF1 activity from its broader antioxidant noise, strengthening mechanistic credibility.
Limitations are meaningful: all data are preclinical (murine in vivo, immortalized hepatocyte line), resveratrol's notoriously poor oral bioavailability in humans is unaddressed, and pretreatment protocols don't map cleanly onto emergency heatstroke intervention. Still, as climate-driven heat illness rises globally, identifying a dietary compound with a specific, druggable hepatoprotective mechanism is more than incremental — it's a credible translational lead worth pursuing in human pharmacokinetic studies.
