Phytochemicals at the PPAR–NF‐ κ B Interface: A Structured Narrative Review of Receptor Pharmacology, Inflammatory Signaling, and Translational Barriers
Sabi Ur Rehman, Fazal Ur Rehman, Shafi Ullah Khan, Amir Zeb, Saleha Ashfaq, Shakir Ullah Khan, Waheed Ullah HafizBackground
The peroxisome proliferator‐activated receptors (PPARs) and nuclear factor‐ κ B (NF‐ κ B) signaling axis serves as master molecular interface governing metabolic homeostasis and inflammatory resolution. Dysregulated reciprocal repression between PPAR‐ α / γ and NF‐ κ B contributes to chronic inflammatory diseases, metabolic syndrome, and malignancy. Synthetic full agonists (e.g., thiazolidinediones and fibrates) are associated with clinical liabilities including adipogenesis, fluid retention, hepatotoxicity, and cardiovascular adverse effects, underscoring the need for safer modulators.
Objective and Rationale
This structured narrative review provides a rigorous mechanistic synthesis of plant derived phytochemicals with selective PPAR modulator (SPPARM) like pharmacology. We elucidate how distinct chemical classes may achieve targeted NF‐ κ B transrepression with reduced transcriptional liability, summarize available ligand receptor binding data, and critically evaluate translational hurdles.
Methods
A structured narrative review was conducted using a systematic style literature search across PubMed/MEDLINE, Scopus, and Web of Science from January 2000 through March 2026. In line with PRISMA 2020 principles for transparent reporting, original research articles were prioritized according to evidence type (clinical, preclinical, in vivo, and in vitro/in silico), with emphasis on pharmacodynamic metrics, binding kinetics (K i , EC 50 , and IC 50 ), receptor dependency validation (knockout, antagonism), and pharmacokinetic data.
Results
Chemically diverse phytochemicals including flavonoids, neolignans, stilbenoids and terpenoids exhibit partial or subtype selective PPAR agonism in reporter and binding assays. Mechanistically, many favor anti‐inflammatory transrepression over full coactivator‐dependent transactivation, with evidence for corepressor recruitment and inhibition of NF‐ κ B nuclear translocation in selected models. However, integrated analysis reveals a persistent disconnect between submicromolar in vitro potency and negligible systemic exposure of free parent compound (low C max , extensive glucuronidation/sulfation), compounded by frequent reliance on unvalidated docking simulations and PPAR‐independent NF‐ κ B inhibition.
Conclusion
Phytochemicals with SPPARM‐like pharmacology represent a promising but unvalidated paradigm for nonsteroidal inflammation control. Realizing their potential will require next‐generation delivery systems (e.g., liposomes, nanoemulsions, and cyclodextrin complexes), mandatory genetic or pharmacological receptor validation, and biomarker‐driven clinical trials that document target engagement at achievable human exposure levels.