Multi-target synergistic mechanisms of flavonoid compounds from traditional Chinese medicine in non-alcoholic fatty liver disease: insights for human and veterinary medicine

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Abstract
Introduction: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder characterized by dysregulated hepatic lipid metabolism, with a continuously rising global incidence and limited safe and effective therapeutic options. Importantly, NAFLD-like conditions, namely hepatic lipidosis or fatty liver syndrome, also prevail in veterinary clinical practice, affecting companion animals (obese cats and dogs) and livestock (periparturient dairy cows, fattening pigs, and broiler chickens). These metabolic liver disorders are primarily induced by inappropriate feeding management and metabolic stress, leading to reduced production performance and survival rate of animals, huge economic losses to the livestock industry, and impaired health of companion animals. Flavonoid compounds derived from traditional Chinese medicine (TCM) possess the advantages of low toxicity and multi-target pharmacological effects, and have emerged as promising natural agents for NAFLD amelioration. Methods: This study adopted a systematic review approach to comprehensively collect, sort out, and summarize recent relevant research findings. We focused on widely reported TCM flavonoids, including quercetin, apigenin, and luteolin, and systematically analyzed the diverse molecular pathways and potential mechanisms by which these compounds exert protective effects against NAFLD and veterinary fatty liver diseases. Results: Existing research evidence demonstrates that TCM flavonoids improve NAFLD through multiple core regulatory pathways. These compounds reverse hepatic lipid metabolism disorders by activating the AMPK/SIRT1 and PPARα signaling pathways, inhibit lipogenesis by suppressing the key lipogenic factor SREBP-1c , and accelerate lipid catabolism by promoting fatty acid β -oxidation. In addition, flavonoids effectively alleviate hepatic oxidative stress, inhibit inflammatory responses, and delay the progression of liver fibrosis. Furthermore, they exert protective effects via regulating novel mechanisms, including cellular autophagy, ferroptosis, and intestinal microbiota homeostasis. Discussion: The multi-target and systematic regulatory characteristics of TCM flavonoids make them excellent candidate natural drugs for NAFLD intervention in both human and veterinary medicine. Nevertheless, several limitations and challenges remain in current research, including low bioavailability of flavonoids and unclear synergistic effects among different flavonoid components. Future studies should focus on improving the bioavailability of flavonoids, elucidating their synergistic molecular mechanisms, and exploring species-specific pharmacokinetic characteristics in cats, dogs, and cattle. Moreover, the development of practical and palatable preparations such as feed additives is essential to promote the clinical translation and large-scale application of flavonoids for the prevention and treatment of NAFLD in human and veterinary clinical practice.

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