Safranal Improves the Anticancer Efficacy of Sorafenib Via Transcriptomic Reprogramming and Metabolomic Changes in a Rat Model of Diethylnitrosamine-Induced Cirrhosis–hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Sorafenib (SB) remains an option for advanced HCC in patients who cannot receive, or do not respond to, immunotherapy. Safranal (SF), a bioactive saffron compound, possesses anti-inflammatory and anticancer properties. This study evaluated SF with SB in a diethylnitrosamine-induced cirrhosis–HCC rat model. Rats were assigned to control, HCC, HCC + SB, HCC + SF, and HCC + SF + SB groups and treated for three weeks. Liver morphology, function, histology, apoptosis, cell proliferation, transcriptomics, and metabolomics analyses were assessed. Combination therapy inhibited hepatic nodules and restored liver architecture. Biochemical and histopathological analyses confirmed improved liver function, reduced fibrosis, vacuolation, and decreased α-SMA expression. Combined treatment improved apoptosis, antiproliferative effects and caused G2/M cell cycle arrest. Inflammatory markers (TNF-α, NF-κB, COX-2, MMP9, and β-catenin) were downregulated. Multiomics confirmed modulation of apoptosis, inflammation, oxidative stress, and metabolic pathways. SF potentiates a promising anti-HCC therapeutic efficacy of SB.