Ginsenoside Rg3 potentiates cisplatin antitumor activity while mitigating nephrotoxicity through SIRT1‑mediated suppression of the NLRP3 inflammasome

Lung cancer is one of the most common causes of cancer‑related mortality worldwide, with cisplatin (CP) being a key chemotherapeutic agent. However, its use is limited by nephrotoxicity and drug resistance. Ginsenoside Rg3 (Rg3) has anticancer properties and potential protective effects on normal tissues. The present study investigated the therapeutic effect of Rg3 and CP in suppressing the proliferation of lung carcinoma cells (LLCs) and inhibiting tumor growth, using both in vitro and in vivo models. LLC cells were exposed to Rg3 and/or CP and the effects on cell proliferation were measured by MTT assay. Tumor‑bearing mouse models were constructed to evaluate the impact on tumor growth. Modulation of biological pathways was analyzed using flow cytometry, western blotting and immunohistochemistry. Co‑treatment with Rg3 and CP enhanced apoptosis in LLC cells and tumor tissues by upregulating cleaved caspase‑3/9 and phosphorylated (p‑)p53, while suppressing vascular cell adhesion molecule 1, intercellular adhesion molecule 1 (ICAM1), macrophage migration inhibitory factor (MIF) and p‑p65 activation. The downregulation of Organic Cation Transporter 2 (OCT2) and P‑glycoprotein (P‑gp) expression in renal tissues of xenograft mice by Rg3 may explain its dual effects in alleviating CP nephrotoxicity and reversing drug resistance. Mechanistic studies in HK‑2 cells demonstrated that Rg3 (80 µg/ml) attenuated CP‑induced NLRP3 inflammasome activation (NLRP3, apoptosis‑associated speck‑like protein with CARD (ASC), caspase‑1) and p‑p65 expression; these effects were reversed by the SIRT1 inhibitor Ex527, implicating SIRT1 pathway dependency. Molecular docking provided a hypothetical model for binding of Rg3 to SIRT1 (‑7.492 kcal/mol) and NLRP3 (‑6.764 kcal/mol), providing a structural basis for the regulatory interactions. Rg3 showed potential as a renal protector, anti‑inflammatory agent and adjunct to CP chemotherapy. The combination offers a promising therapeutic strategy for lung cancer by enhancing efficacy and decreasing nephrotoxicity. Further investigation into mechanisms and long‑term effects is warranted.