Mechanistic Biological Insights into the Effects of Resveratrol and Nano-Resveratrol on EAT-Induced Hepatorenal Damage

Background/Objectives: Malignant ascites is characterized by extensive tumor dissemination within the peritoneal cavity, abnormal fluid accumulation, and progressive multiorgan dysfunction, including hepatic and renal impairment. Methods: The present study was conducted to evaluate the protective effects of resveratrol (RSV) and its nanocrystal formulation (NANO-RSV) at doses of 25 and 50 mg/kg against Ehrlich ascites tumor (EAT)-induced hepatic and renal injury by assessing proliferating cell nuclear antigen (PCNA) expression and apoptosis/necrosis rates, which are key indicators of tissue injury, repair, and regeneration. In addition, microvessel density (MVD) was evaluated in peritoneal tumor tissue, liver, and kidneys to assess angiogenesis and tissue remodeling, while macrophage polarization in the spleen was examined to determine the immunomodulatory effects of RSV and NANO-RSV. Results: Resveratrol and its nano formulations acted as potent inhibitors of EAT cells growth through downregulation of PCNA expression, leading to increased tumor cell death via apoptosis and secondary necrosis. In EAT-bearing mice, the hypoxic microenvironment was associated with increased PCNA expression, enhanced angiogenesis, and reduced apoptosis in hepatic tissue. In contrast, treatment with resveratrol and nano-resveratrol reduced PCNA expression, increased apoptotic activity, suppressed angiogenesis, and induced hepatic steatosis. Progression of steatosis, particularly in resveratrol-treated animals, was associated with impaired hepatic regenerative capacity. In the kidneys, elevated PCNA expression and increased cell death indicated active tissue injury accompanied by compensatory proliferative responses. Furthermore, increased splenic arginase-1 activity correlated with enhanced tissue damage and activation of M2 macrophage-mediated repair mechanisms. Conclusions: In conclusion, resveratrol exhibits significant antitumor activity but may induce organ toxicity, whereas its nanocrystals formulation demonstrates improved safety while maintaining efficacy. Enhanced stability, bioavailability, and sustained-release properties of nano-resveratrol contribute to reduced hepatic and renal injury compared with native resveratrol.