Natural Products as Multi-Targeted Therapeutic Agents Against Chronic Inflammatory and Metabolic Disorders

Abstract

Chronic inflammatory and metabolic disorders—type 2 diabetes mellitus (T2DM), obesity, non-alcoholic fatty liver disease (NAFLD/MASLD), atherosclerosis and the metabolic syndrome—are no longer viewed as separate entities but as manifestations of a shared pathophysiology termed “metaflammation”: a chronic, low-grade inflammatory state driven by over-nutrition that is inseparably coupled to metabolic dysregulation. Because this network is multifactorial and self-amplifying, single-target pharmacology is often insufficient, and there is growing interest in multi-targeted agents. Natural products—polyphenols, flavonoids, alkaloids, terpenoids and isothiocyanates such as berberine, curcumin, resveratrol, EGCG, quercetin, sulforaphane and silymarin—are archetypal polypharmacological molecules that simultaneously engage the master regulators sitting at the inflammation–metabolism interface: the energy sensor AMPK and the deacetylase SIRT1, the pro-inflammatory hub NF-κB and the NLRP3 inflammasome, the antioxidant transcription factor Nrf2, and the lipid-metabolic regulators PPARα/γ.
This review integrates the mechanistic and clinical evidence for this class, mapping how individual compounds coordinate anti-inflammatory, insulin-sensitising, lipid-lowering and antioxidant actions. Pooled clinical data are substantial: berberine, for example, produces statistically significant reductions in fasting glucose, HbA1c, HOMA-IR and the inflammatory markers IL-6, TNF-α and CRP across meta-analyses of randomised trials, while curcumin, resveratrol and silymarin improve distinct cardio-metabolic parameters. The principal barrier to translation is poor oral bioavailability, which modern nanoformulation and delivery strategies are increasingly able to overcome. The review concludes that multi-targeted natural products are rational, evidence-supported candidates for the integrated management of metaflammation, provided their pharmacokinetic limitations and the need for standardisation and definitive clinical trials are systematically addressed.