Bioactive nanoparticles from clam extracts mitigate alcoholic liver injury by modulating multiple pathways.

Alcoholic fatty liver disease (AFLD) is a global health burden driven by ethanol-induced steatosis, inflammation, and oxidative stress. Clam extracts have demonstrated hepatoprotective potential, attributed to abundant bioactive compounds. In this work, clam (Geloina erosa)-derived nanoparticles (CNPs) were isolated via tangential flow filtration and characterized as 62.2 ± 3.0 nm, negatively charged nanoscale particles enriched in phospholipids, diacylglycerols, and bioactive metabolites. Oral administration of CNPs for nine weeks in ethanol-fed mice significantly alleviated ethanol-induced liver injury. CNPs modulated hepatic inflammation by downregulating TLR4/MyD88 signaling and pro-inflammatory cytokines, rebalanced lipid metabolism through suppression of SREBP-1c and activation of PPARα, and restored antioxidant defenses by reactivating the Nrf2/HO-1 pathway. Moreover, CNPs enhanced ethanol detoxification by upregulating ADH and ALDH while inhibiting CYP2E1, and promoted a macrophage phenotype shift toward M2. Restoration of fecal short-chain fatty acids and intestinal retention supported their gut-liver axis activity. These findings suggest that CNPs act as multifunctional nanocarriers delivering endogenous bioactives for AFLD mitigation.