Newly Identified Peptide (IDQSILTGESVSVIK) From Pinctada martensii Alleviates Acute Alcohol‐Induced Liver Injury via Coupled ADH/ALDH Activation and CYP2E1 Suppression

Alcoholic liver disease (ALD) presents a severe global health challenge, making the development of safe and effective natural hepatoprotective substances of significant value. Although Pinctada martensii meat is rich in bioactive compounds, its specific anti‐ALD peptides have rarely been reported. To address this, we integrated surface plasmon resonance (SPR) targeting ADH with Q‐Exactive to systematically screen and identify novel hepatoprotective peptides from P. martensii extracts. Four potential active peptide sequences were identified: VGLTNYAAAYCTGLLLAR (V‐18), TITLEVEPSDTIENVK (T‐16), IDQSILTGESVSVIK (I‐15), and MQIFVK (M‐6). In vitro evaluations of the synthesized peptides revealed that I‐15 and T‐16, at 100 μΜ, effectively restored ethanol‐impaired LO2 cell viability, increasing it by 28.65% and 26.58%, respectively. These peptides significantly reduced ALT activity, AST activity, MDA content, and TG content, while increasing SOD and GSH levels ( p < 0.01), demonstrating excellent cytoprotective effects. Further animal experiments revealed that oral administration of I‐15 (100 mg/kg) markedly ameliorated liver index abnormalities and histopathological lesions. I‐15 exerted its hepatoprotective effects by accelerating ethanol metabolism, enhancing the activity of hepatic ADH and ALDH ( p < 0.01), increasing the antioxidant indicators SOD and CAT activity ( p < 0.01), reducing serum AST, and hepatic MDA, TG, and CYP2E1 levels ( p < 0.01), and effectively alleviating liver histopathological damage. Overall, this study highlights I‐15 as a promising marine bioactive agent for alleviating alcohol‐induced liver injury, providing a structural basis for novel functional foods or hepatoprotective peptide candidates.