Background:

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-related mortality worldwide. Exploring novel preventive and therapeutic strategies is thus imperative. This study evaluated the therapeutic and protective effects of boswellic acid (BA), both alone and in combination with low-dose gamma radiation, against diethylnitrosamine (DEN)-induced HCC in male albino rats.

Methods:

A total of 90 rats were randomly assigned to 5 groups: Control, DEN, DEN + BA, DEN + Radiation, and DEN + Radiation + BA. Liver carcinogenesis was induced with DEN (20 mg/kg, administered orally for 6 weeks). BA (250 mg/kg) was administered orally for 8 weeks following cancer induction. Radiation (0.5 Gy, twice over 2 weeks) was applied to relevant groups after tumor induction. The study assessed serum biochemical markers, including colorimetric detection of liver enzymes (ALT and AST), oxidative stress markers (malondialdehyde, SOD activity), ELISA detection inflammatory cytokines Nuclear factor kappa-light-chain-enhancer of activated B cells, Tumor necrosis factor alpha (NF-κB and TNF-α), and the expression level of proliferation marker Janus kinase, Signal transducer and activator of transcription 3, Mitogen-activated protein kinase (JAK, STAT-3, and MAPK), via qRT-PCR, angiogenesis Vascular Endothelial Growth Factor, transforming growth factor beta (VEGFA, TGF-β), levels of apoptotic marker (Caspase-3, and Granzyme B) and Bax (Bcl-2-associated X protein), Bcl-2 (B-cell lymphoma 2) by ELISA. Histopathological examination was performed to evaluate tissue alterations.

Results:

Results demonstrated that BA, especially when combined with radiation, improved hepatic histopathology, reduced liver injury, suppressed oxidative stress and inflammation (NF-κB and TNF-α), and promoted apoptosis evidenced by increased Bax, caspase-3, granzyme B levels associated with significant decrease in Bcl-2 level. The combined treatment also inhibited tumor proliferation and angiogenesis by downregulating the expression levels of (JAK/STAT3, MAPK), VEGF-A, and TGF-β concentrations. These findings suggest that BA, synergistically with low-dose gamma radiation, offers a promising strategy for HCC therapy, supporting its potential as an adjuvant in HCC management.

Graphic Abstract

Boswellic acid (BA) with low-dose gamma radiation mitigates DEN-induced hepatocellular carcinoma in rats, improving liver histology, reducing oxidative stress and inflammation, promoting apoptosis, and inhibiting proliferation and angiogenesis (JAK/STAT3, MAPK, VEGF-A, TGF-β). BA + radiation shows strongest therapeutic potential.