Carob pod aqueous extract potentiates cisplatin efficacy and reduces toxicity in experimental hepatocellular carcinoma via mitochondrial and inflammatory pathway modulation

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BACKGROUND: Hepatocellular carcinoma (HCC) is a global health challenge with limited therapeutic options. The effectiveness of conventional medication like cisplatin is often compromised by their severe toxicity. This study investigated carob pod aqueous extract (CPAE), a polyphenol-rich natural product, as a potential adjunct therapy to enhance efficacy and mitigate cisplatin toxicity in a preclinical HCC animal model. METHODS: A rat model of HCC was established using diethylnitrosamine (DEN) and carbon tetrachloride (CCl₄). Forty-two Wistar rats were divided into seven groups, receiving various treatments: control, CPAE, vehicle, HCC only, HCC+CPAE, HCC+cisplatin, and HCC+CPAE+cisplatin. Liver and kidney function, metabolic profiles, oxidative stress/antioxidant parameters, gene and protein expression (AMPK, PGC-1α, TFAM, SIRT1, iNOS, NF-κB, IκK, p53, SREBP-2), histopathology, and statistical analyses were performed. RESULTS: HCC induction caused significant liver dysfunction, metabolic disturbances, oxidative stress, alongside dysregulation of AMPK/PGC-1α/TFAM and NF-κB/iNOS pathways. CPAE, alone or with cisplatin, markedly ameliorated these changes, improving liver and kidney function, restoring antioxidant status, reducing the tumor marker AFP, suppressing pro-inflammatory and oncogenic signaling, and enhancing histological architecture. Furthermore, Combination therapy demonstrated synergistic benefits, with CPAE reducing cisplatin-induced nephrotoxicity and enhancing its antitumor efficacy, primarily via modulation of mitochondrial biogenesis, redox balance, and inflammatory signaling. CONCLUSIONS: CPAE exhibits potent hepatoprotective and anti-HCC activity, especially when combined with cisplatin. This combination modulates mitochondrial and inflammatory pathways while mitigating cisplatin-induced toxicity. These finding position CPAE as a promising natural adjuvant for integrative HCC management. Further translational studies are warranted to validate these findings and explore clinical applicability.

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