Hepatotoxicity of Nonesterified Fatty Acids to Dairy Cows: Pathophysiological Mechanisms and Prospective Solutions

ABSTRACT Circulating concentrations of nonesterified fatty acids (NEFAs) are elevated due to lipid mobilization from adipose tissue in periparturient dairy cows. Although this metabolic adaptation facilitates energy homeostasis under the negative energy balance condition, sustained systemic NEFA overload induces profound hepatic impairment. Emerging evidence identifies excessive NEFAs to be the pathophysiological cornerstone of periparturient disorders; however, the precise molecular mechanisms underlying NEFA‐induced hepatotoxicity remain incompletely characterized, hindering the development of effective preventive and therapeutic strategies. This literature review synthesizes contemporary insights into key cellular pathways implicated in NEFA‐mediated hepatotoxicity: disorders in lipid and carbohydrate metabolism, impairment of autophagy, excessive inflammatory response, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, and finally, cell death. Critical analysis reveals two underexplored dimensions in current research paradigms: (1) The dynamic composition of circulating NEFAs modulates hepatotoxic potency through differential membrane incorporation and signaling pathway activation, suggesting that improving blood NEFA composition through dietary fat supplementation offers a potential strategy; and (2) the periparturient inflammatory milieu potentiates NEFA toxicity, suggesting targeted anti‐inflammatory interventions ameliorate transition period adaptation. Consequently, this review advances our mechanistic understanding while providing translational frameworks for improving periparturient management through precision nutrition and therapeutic development.