The current study was conducted to determine the precise mechanisms of Sirtuin-1 (Sirt-1), TGF- β (Transforming Growth Factor-β), and long non-coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (LncRNA MALAT-1) in signaling pathways in doxorubicin (DOX)-induced nephrotoxicity. The potential therapeutic effect of Resveratrol and Pirfenidone in DOX toxicity was also assessed. Thirty-six male adult rats were evenly distributed into four groups: Group 1: control rats. Group 2: DOX exposed rats’ group, each animal received
7.5 mg/kg DOX as a single intravenous dose, Group 3: DOX exposed group subjected to oral resveratrol (20 mg/ kg/daily for two weeks), Group 4: DOX exposed group subjected to oral Pirfenidone (200 mg/kg once daily for 10 days). At the planned time, animals were sacrificed. Renal tissue was collected to assess matrix metalloproteinase-9 (MMP9), inflammatory and apoptotic markers: tumor necrosis factor-alpha (TNF- β, caspase- 3, cyclo-oxygenase-2 (COX-2), and oxidative stress markers: nitric oxide (NO), Glutathione (GSH), malondial- dehyde (MDA), and superoxide dismutase (SOD). Sirtuin-1 (Sirt-1), TGF-β, and LncRNA MALAT-1 were quan- titatively assessed by real-time RT-PCR in the whole blood. Results showed that the DOX group exhibited a significant increase in oxidative stress markers, and inflammatory, and apoptotic markers in the renal tissue. Histologically, the renal tubule lining cells exhibited vacuolar alterations in the cytoplasm, glomerular atrophy, and vascular congestion. Furthermore, renal degeneration was evident, as confirmed by the heightened immuno- expression of MMP9. Exposure to DOX resulted in a significant decrease in Sirtuin-1 (Sirt-1) with a significant increase in the TGFβ, and LncRNA MALAT-1 gene expression. However, pre-treatment with either resveratrol/or Pirefenidone ameliorated the histological renal alterations, regulated the pathways of Sirt-1, TGFβ, and LncRNA MALAT-1, and decreased all oxidative stress, inflammatory and apoptotic markers. In conclusion, DOX exposure leads to renal toxicity by inducing renal degeneration, oxidative stress, and apoptosis. Administration of either resveratrol or Pirfenidone counteracted these changes and protected the kidney against DOX-induced renal damage.