Integrated <i>In Vivo</i> and <i>In Silico</i> Approaches for Targeting JAK2/STAT3/SOCS3: Repurposing Boeravinone B and Resveratrol as Chemopreventive Agents in Colon Cancer

Colon cancer ranks among the most prevalent malignancies worldwide and contributes substantially to cancer-related mortality. This study employed an integrated approach to evaluate the chemopreventive effects of Boeravinone B (BB) and Resveratrol (REV), administered individually and in combination, in the azoxymethane (AOM)-induced rat model of colon cancer, with particular emphasis on cytokine signaling pathways and mitochondrial regulation of apoptosis. The combination of BB (15 mg/kg) and REV (8 mg/kg) exhibited greater efficacy than either treatment alone. These combined treatments (BB + REV) significantly reduced pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor-alpha [TNF-α]), nitro-oxidative stress indicators (NO, iNOS), and histological damage, while promoting mitochondria-mediated apoptosis via modulation of BAX and BCL2. Network analysis revealed that centrality metrics (betweenness, closeness, degree, and stress centrality), identified STAT3, SOCS3, JAK2, BAX, and BCL2 as key hub proteins involved in cytokine signaling and apoptotic pathways. These nodes exhibited the highest centrality values (betweenness: 0.046667 for STAT3/SOCS3/JAK2; degree: 10 for all five proteins), indicating their pivotal roles as therapeutic targets. Molecular docking revealed favorable binding affinities of BB for SOCS3 (−9.0 kcal/mol), BAX (−9.0 kcal/mol), JAK2 (−8.1 kcal/mol), and STAT3 (−7.8 kcal/mol). In comparison, REV exhibited its highest binding affinities for SOCS3 (−7.2 kcal/mol) and BAX (−7.0 kcal/mol). These findings identify SOCS3, BAX, JAK2, and STAT3 as potential molecular targets mediating the combined treatment’s anti-inflammatory and pro-apoptotic effects. This integrated in vivo and in silico study showed that combined BB and REV exerted a stronger chemopreventive effect against AOM-induced colon cancer via complementary mechanisms: restoring mitochondrial adenosine triphosphate synthase (ATPase) activity, suppressing biomarkers of inflammation, nitro-oxidative stress, and apoptosis, with strong binding affinities. These findings support repurposing BB and REV as a multitargeted combination therapy against colon cancer.