Shahrekord University of Medical Sciences Journal of Herbmed Pharmacology 2345-5004 15 2 2026 04 01 Integrated in silico, in vitro, and in vivo exploration of Nephrolepis cordifolia for type 2 diabetes mellitus therapy 217 229 10.34172/jhp.2026.53362 EN Samsul Hadi https://orcid.org/0000-0001-9929-0623 Deni Setiawan https://orcid.org/0000-0001-7991-6238 Noer Komari https://orcid.org/0000-0003-4860-9408 Askur Rahman https://orcid.org/0000-0003-1700-7383 Kunti Nastiti https://orcid.org/0000-0003-0877-6789 Noval Noval https://orcid.org/0000-0001-6377-9662 Hadi Kuncoro https://orcid.org/0000-0002-3406-522X Journal Article 10.34172/jhp.2026.53362 2025 08 25 2025 11 23 Introduction: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction, while current pharmacological therapies often show limited efficacy and adverse side effects. Nephrolepis cordifolia is a traditional medicine used to treat metabolic and inflammatory diseases. This study aimed to investigate the antidiabetic potential of N. cordifolia through an integrative approach of in silico, in vitro, and in vivo to elucidate the molecular mechanisms against T2DM. Methods: This study began with an in vitro assay to evaluate the ability of N. cordifolia to inhibit glucose release through amylolysis kinetics. In vivo experiments involved alloxan-induced diabetes in Wistar rats, which were administered extract doses of 200, 400, and 600 mg/kg to assess blood glucose levels and pancreatic histology. Meanwhile, in silico analysis identified genes expressed through GEO2R and performed molecular docking to explore potential antidiabetic mechanisms. Results: The ethyl acetate fraction of N. cordifolia effectively lowered glucose levels, showing the highest glucose dialysis retardation index (GDRI) value (82.56). In vivo tests demonstrated that the ethanol extract significantly reduced blood glucose levels (P < 0.05) and improved pancreatic histology at a dose of 600 mg/kg. Gene analysis revealed involvement in the diabetic cardiomyopathy pathway, with ellagic acid as the most active compound, exhibiting strong and stable binding to mitochondrial targets, including NDUFA9 and NDUFS4. Conclusion: N. cordifolia has potential as a natural product therapy candidate for the management of T2DM through specific molecular mechanisms.