1Department of Pharmacology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, India. Email: hod.phacol.ktr.med@srmist.edu.in. ORCID: 0000-0002-2797-7888
Email: sathyanv@srmist.edu.in. ORCID: 0000-0003-0713-5576
*Corresponding author: Dr Jerin James, Department of Pharmacology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, India. Email: jerinjames06@gmail.com. ORCID: 0000-0002-5534-9299
Received: 12th Dec, 2025; Revised: 12th Feb 2026; Accepted: 13th Feb, 2026; Available Online: 10th March, 2026
Background: Major depressive disorder (MDD) is a multifactorial neuropsychiatric condition with strong links to inflammation and metabolic imbalance. Conjugated linoleic acid (CLA), a bioactive fatty acid found in ruminant-derived foods, has been implicated in neuroinflammatory and lipid regulatory mechanisms. However, its molecular targets and signaling pathways in MDD remain poorly characterized.
Methods: A comprehensive in silico framework integrating pharmacokinetic evaluation, network pharmacology, and enrichment analysis was used to elucidate CLA's potential mechanism of action against MDD. Pharmacokinetic parameters were predicted using SwissADME and pkCSM. Putative CLA targets were identified through SwissTargetPrediction, while MDD-associated genes were retrieved from GeneCards. Overlapping targets were determined and subjected to STRING network construction, Cytoscape/CytoHubba topological analysis, and DAVID 2021 enrichment for Gene Ontology (GO) and KEGG pathways.
Results: CLA satisfied key drug-likeness criteria with high gastrointestinal absorption, positive blood–brain barrier permeability, and a bioavailability score of 0.85, indicating excellent oral and CNS exposure. Ninety-one overlapping targets were identified between CLA and MDD genes, forming a protein–protein interaction (PPI) network of 91 nodes and 431 edges. Hub-gene analysis revealed ten core regulators: PPARG, PPARA, PPARD, FASN, SCD, FABP4, ACACB, DGAT1, TNF, and PTGS2. Functional enrichment highlighted significant biological processes such as regulation of the ERK1/ERK2 cascade, inflammatory response, and apoptosis control. Cellular components were mainly localized to the plasma membrane, cytosol, and nucleus, while molecular functions involved nuclear receptor activity, lipid binding, and serine-type endopeptidase activity. KEGG pathway analysis revealed that CLA primarily acts through the PPAR signaling pathway, serotonergic synapse, neuroactive ligand–receptor interaction, and TNF signaling. These pathways jointly regulate lipid metabolism, neurotransmission, and inflammatory tone—processes central to MDD neurobiology.
Conclusion: This study provides a mechanistic basis for CLA's antidepressant potential through multi-target regulation of metabolic–inflammatory cross-talk. By activating PPAR-mediated transcription and modulating TNF-driven inflammation, CLA may restore neuronal energy homeostasis and synaptic plasticity. The integrative pharmacokinetic and network evidence positions CLA as a promising nutraceutical candidate for adjunctive management of MDD.
Keywords: Conjugated linoleic acid (CLA); Major depressive disorder (MDD); Network pharmacology; PPAR signaling; TNF pathway; Immunometabolic regulation; Neuroinflammation; Bioinformatics; DAVID enrichment; Cytoscape analysis
How to cite this article: James J, Rani J, Varadarajan S. Integrative Network Pharmacology And Bioinformatics Analysis Reveal The Antidepressant Potential Of Conjugated Linoleic Acid Via PPAR-Mediated Immunometabolic Modulation. Int J Drug Deliv Technol. 2026;16(3): 500-521. DOI: 10.25258/ijddt.16.3.59
Source of support: Nil.
Conflict of interest: None