Baicalin Alleviates Lactational Heat‐Stress‐Induced Hepatic Mitochondrial Dysfunction via Sirt3‐Dependent Deacetylation of NDUFS1

ABSTRACT Lactation represents one of the most metabolically demanding physiological states in mammals, characterized by heightened bioenergetic flux that increases electron transport chain (ETC) activity. This metabolic feature renders the maternal liver highly susceptible to mitochondrial redox imbalance under heat stress (HS). Baicalin (BAI), a nature food‐derived flavonoid from Scutellaria baicalensis , is known for its antioxidant and hepatoprotective properties, but its mechanism in lactational HS has not been fully elucidated. Here, we demonstrate that BAI exerts its hepatoprotective effects by targeting the Sirt3–NDUFS1 axis to preserve mitochondrial complex I redox homeostasis in lactating mammals. Using a lactational HS mouse model and AML‐12 hepatocytes, we demonstrate that BAI attenuates HS‐induced hepatic injury, oxidative stress, and mitochondrial dysfunction. Mechanistically, BAI restored the expression of the mitochondrial deacetylase Sirt3, which was suppressed by HS. This led to deacetylation of the complex I core subunit NDUFS1, thereby rescuing complex I activity and limiting mitochondrial reactive oxygen species (mtROS) overproduction. BAI also attenuated secondary excessive Pink/PARKIN‐dependent mitophagy triggered by mitochondrial respiratory failure, revealing coordinated recovery of electron transport function and downstream mitochondrial quality control. Pharmacological inhibition of Sirt3 abolished the protective effects of BAI on mitochondrial respiration and redox balance, confirming Sirt3 dependence. These findings reveal a BAI–Sirt3–NDUFS1 axis maintaining mitochondrial complex I redox homeostasis, thereby enhancing maternal hepatic resilience to HS. Distinct from previous Sirt3 research in nonreproductive disease models, this work establishes a natural nutritional target strategy specialized for HS lactating subjects, with great potential for maternal nutritional intervention and functional food development.