Plant compounds may rewire immune metabolism in heart disease, evidence still thin

Cardiovascular diseases remain the leading cause of death worldwide, accounting for roughly a third of all global fatalities, and a persistent problem has haunted cardiologists for years: even when patients hit their cholesterol and blood pressure targets, many still suffer recurrent heart attacks and strokes. A new mini-review published in Frontiers in Cardiovascular Medicine argues that the missing piece may be chronic low-grade inflammation driven by a two-way conversation between cellular metabolism and immune activity, a field known as immunometabolism. The review, authored by researchers at the Patanjali Research Foundation and Gurukula Kangri University in Haridwar, India, examines whether plant-derived compounds could be engineered into therapies that target this metabolic-immune crosstalk in cardiovascular disease.

The core idea of immunometabolism is that metabolic states do not merely fuel immune cells; they program them. Under resting conditions, naïve T cells, regulatory T cells, tissue-resident macrophages and dendritic cells rely mainly on mitochondrial oxidative phosphorylation and fatty acid oxidation to maintain immune balance. When inflammation strikes, however, immune cells undergo a dramatic metabolic reprogramming toward glycolysis, the same Warburg-style shift seen in cancer cells. Although glycolysis generates less ATP than oxidative phosphorylation, it supplies the metabolic intermediates needed to build the nucleotides, amino acids and lipids required for pro-inflammatory cytokines and reactive oxygen species. In short, pro-inflammatory immune responses run on sugar, while tissue repair and inflammatory resolution run on fat oxidation.

This metabolic switch matters enormously in cardiovascular disease. In atherosclerotic plaques, oxidized LDL triggers macrophages to alter glycolysis, lose tricarboxylic acid cycle function and accumulate immunometabolites such as succinate, citrate and fumarate, which activate hypoxia-inducible factor-1 alpha, NF-κB and the NLRP3 inflammasome, sustaining inflammatory cytokine production. Concomitant mitochondrial dysfunction, reactive oxygen species generation, impaired cholesterol efflux and defective mitophagy drive foam-cell formation and plaque progression. Chronic hypercholesterolaemia can even induce trained immunity, a state in which metabolic and epigenetic remodelling keeps macrophages persistently activated long after the initial insult. Meanwhile, pro-inflammatory Th1 and Th17 cells thrive in glycolytic environments, whereas regulatory T cells depend on oxidative metabolism for immune tolerance, so metabolic dysregulation undermines their suppressive capacity and fuels vascular inflammation.

Several molecular pathways sit at the centre of this network. AMP-activated protein kinase, the cell’s energy sensor, promotes fatty acid oxidation, mitochondrial biogenesis and autophagy while suppressing inflammatory signalling; reduced AMPK activity is associated with increased glycolytic energy production, endothelial malfunction and macrophage-driven inflammation. Mechanistic target of rapamycin, by contrast, drives anabolism, glycolysis and pro-inflammatory immune responses during nutritional surplus, and its persistent activation contributes to chronic inflammation, impaired autophagic flux, endothelial dysfunction and adverse cardiac remodelling. NF-κB links metabolic stress to inflammatory gene induction, switching on TNF-alpha, IL-1, IL-6, COX-2 and iNOS in response to reactive oxygen species, dyslipidaemia, mitochondrial dysfunction and high glucose. The NLRP3 inflammasome, activated by cholesterol crystals, oxidized LDL and mitochondrial ROS, matures interleukin-1 beta and interleukin-18 and triggers pyroptosis. SIRT1 restrains NF-κB signalling and reduces oxidative stress, while NRF2 orchestrates antioxidant defences.

The review’s central proposal is that phytochemicals, with their polypharmacological character, could modulate several of these nodes simultaneously. Curcumin from turmeric, resveratrol from grapes, berberine from Berberis species, quercetin from common fruits and vegetables, and andrographolide from Andrographis paniculata have all shown pathway-specific effects in cellular and animal models of inflammation, oxidative stress, mitochondrial function, macrophage responses and endothelial dysfunction. Berberine, curcumin and resveratrol have been linked to AMPK-associated effects on mitochondrial metabolism and inflammatory signalling. Curcumin, ginsenosides and epigallocatechin gallate have blocked mTOR hyperactivity in experimental studies while restoring AMPK activity and promoting autophagy. Andrographolide, curcumin, resveratrol and baicalein affect NLRP3 inflammasome signalling primarily through mitochondrial oxidative stress, NF-κB priming and autophagic processes, and resveratrol, quercetin, sulforaphane and curcumin activate SIRT1 and NRF2 to stimulate mitochondrial biogenesis, antioxidant defences and mitophagy.

The authors are unusually blunt about the limits of this evidence, and that candour is arguably the review’s most important message. Pathway modulation in cell cultures and animal models should not be confused with demonstrated cardiovascular therapeutic effectiveness. Most existing data come from in vitro studies and animal experiments, while adequately powered randomised clinical trials assessing major cardiovascular events or validated immunometabolic endpoints are scarce; human research has largely evaluated surrogate cardiometabolic risk factors instead. It also remains unclear whether any cardiovascular effects attributed to phytochemicals result from direct modulation of immune-cell metabolism or from secondary changes in systemic glucose and lipid metabolism, oxidative stress or inflammatory status. Mechanistic findings, the review concludes, should be treated as hypothesis-supporting rather than proof of clinical improvement.

Translation faces formidable pharmacological obstacles. Many phytochemicals suffer from poor water solubility, low oral bioavailability, rapid metabolism and limited tissue exposure, meaning the concentrations reached at cardiovascular sites after conventional administration may fall short of those used in laboratory experiments. Phytochemical composition and biological activity vary with plant species, geographic origin, growing conditions, harvest timing, extraction techniques and manufacturing methods, making studies difficult to compare and reproduce. Potential herb-drug interactions add further safety concerns. Nano-phytomedicine, using liposomes, phytosomes, polymeric nanoparticles and lipid-based carriers, has shown in experimental settings the potential to improve stability, apparent bioavailability, cellular exposure and controlled delivery, but whether these formulation gains translate into better cardiovascular outcomes or safety remains to be demonstrated.

The review points to approved drugs as a benchmark for what genuine immunometabolic therapy looks like. Metformin, beyond lowering glucose, activates AMPK, inhibits NF-κB-mediated inflammatory signalling, improves mitochondrial oxidative phosphorylation and polarises macrophages toward the anti-inflammatory M2 phenotype. Rapamycin, an mTOR inhibitor, stimulates autophagy and may reduce pathological ventricular hypertrophy, though chronic immunosuppression limits its broader use. The CANTOS trial provided convincing clinical evidence that canakinumab, an interleukin-1 blocker, reduced recurrent cardiovascular events independently of cholesterol lowering, validating residual inflammation as a therapeutic target in atherosclerosis. SGLT2 inhibitors, originally designed for diabetes, became cardioprotective agents, with proposed mechanisms involving mitochondrial bioenergetics, oxidative stress and inflammasome signalling, though the contribution of each process to their clinical benefit is uncertain. The authors stress these examples support the rationale for immunometabolic targeting but do not prove that phytochemicals are equally effective.

Looking forward, the researchers advocate a disciplined research pipeline: standardised, chemically characterised botanical extracts; thorough pharmacokinetic, pharmacodynamic and safety evaluation including herb-drug interaction assessment; mechanistic validation in disease-relevant cardiovascular models; and well-designed randomised trials that combine clinically meaningful cardiovascular outcomes with immunometabolic biomarkers. Advanced tools, including single-cell RNA sequencing, spatial transcriptomics, metabolomics, proteomics, systems and network pharmacology, multi-omics integration and artificial intelligence-assisted compound discovery, could help identify cell-specific responses and promising molecular targets, though computational predictions must still be validated experimentally and clinically. The authors also suggest classifying plant constituents by their molecular targets rather than their botanical origin, which could clarify modes of action across the crowded field of natural products.

The bottom line is a careful one. Cardiovascular immunometabolism is a biologically plausible and increasingly well-mapped framework connecting obesity, insulin resistance, dyslipidaemia and oxidative stress to vascular inflammation, and phytochemicals genuinely do perturb the relevant pathways in laboratory systems. But the current evidence does not show that phytomedicine pathway modification produces clinically significant cardiovascular benefit, and the review explicitly frames these compounds as promising research prospects rather than established alternatives to evidence-based cardiovascular therapy. Until standardised formulations survive rigorous pharmacokinetic scrutiny and adequately powered randomised trials, the leap from turmeric’s molecular charm to a proven heart medicine remains exactly that: a leap.

Subject of Research: The role of immunometabolism in cardiovascular disease and the potential of phytochemicals to modulate it

Article Title: Targeting cardiovascular immunometabolism with phytomedicines: an emerging therapeutic technique

Article References: Balkrishna, A., Mishra, S., Rana, M., Arya, V., & Singh, S. (2026). Targeting cardiovascular immunometabolism with phytomedicines: an emerging therapeutic technique. Frontiers in Cardiovascular Medicine, 13, 1941655. https://doi.org/10.3389/fcvm.2026.1941655

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1941655

Keywords: cardiovascular disease, immunometabolism, phytochemicals, inflammation, AMPK, NLRP3 inflammasome, curcumin, resveratrol, berberine, macrophages, mitochondrial dysfunction, clinical translation