Fucoidan attenuates alcohol-induced liver injury via PON1/HDL/NF-κB axis

Paraoxonase 1 (PON1) exerts a protective effect against alcoholic liver disease (ALD) by regulating oxidative stress and inflammation. A fucoidan derived from Hizikia fusiformis, JHCF4, is associated with increased nuclear sterol regulatory element-binding protein 2 (SREBP 2) levels and higher PON1/high-density lipoprotein (HDL) expression.

PON1-silenced Kupffer cells were established using small-interfering RNA (siRNA), and protein blot analysis, TUNEL, JC-1, Hoechst 33342, and transmission electron microscopy (TEM) were used to determine the mechanism by which JHCF4 protects against ethanol-induced cellular damage, and the role of PON1, and protein-protein indirect interactions were determined using co-immunoprecipitation (Co-IP). The therapeutic effects of JHCF4 were similarly verified using AAV-shRNA-PON1-transduced C57BL/6 J mice using staining, western blotting analysis, and cytokine assays.

In vivo and in vitro analyses demonstrated that JHCF4 significantly upregulates PON1 and HDL levels within the PON1/HDL/NF-κB pathway and suppresses excessive NF-κB activation within this pathway. Meanwhile, the key role of PON1 in human ALD livers was observed. Thus, validating the potential therapeutic efficacy of JHCF4 targeting the PON1/HDL/NF-κB axis in the treatment of alcoholic liver disease. The Q192R variant (arginine substitution) significantly amplifies PON1's ability to suppress oxidative stress compared to wild-type (Q192). Q192R-related statements as preclinical and hypothesis‑generating. The PON1 (Q192R)-HDL complex demonstrates superior NF-κB pathway inhibition through strengthened interaction with apolipoprotein A-II (apoA-II).

This study elucidates the novel mechanism by which fucoidan derivative JHCF4 exerts ALD therapeutic effects through PON1/HDL/NF-κB axis regulation.