Here, it was demonstrated that the polyphenol-rich leaf extract of P. oceanica (POE) prevents intracellular lipid accumulation and blocks the MAPKs/NF-κB axis, and consequently reduces MMP-2/9 in HG-exposed HepG2 cells, used as an in vitro model of HCC. The gene discussed is NFKB1; the disease is hepatocellular carcinoma.