Potential natural products for the treatment of diabetic cardiomyopathy: Advances and outlooks

Diabetic cardiomyopathy (DCM) is a diabetes‑specific complication characterised by apoptosis, oxidative stress, inflammation, and fibrosis. Early diagnosis is difficult, and current treatments have limited efficacy. Natural products offer diverse structures and multitarget potential. This review summarises recent advances in flavonoids, terpenoids, phenylpropanoids, alkaloids, and polysaccharides for DCM, providing a foundation for drug development.

Introduction

DCM affects ~20% of diabetes patients. Pathologically, it involves apoptosis, oxidative stress, inflammation, and fibrosis, progressing from diastolic to systolic dysfunction. Current therapies have limitations. Natural products, with historical use in TCM, offer diverse structures and favourable safety profiles, making them promising for DCM.

Natural Products for DCM

Flavonoids (C6‑C3‑C6) are the most studied, targeting metabolism, oxidative stress, inflammation, fibrosis, and cell death.

• Flavonols (quercetin, icariin): Reduce inflammation/fibrosis; activate Apelin/Sirt3.

• Flavones (baicalein, galangin): Activate Nrf2; suppress NF‑κB/NLRP3.

• Isoflavones (puerarin): Inhibit NLRP3 pyroptosis via P2X7; improve mitochondrial function.

• Chalcones (phlorizin, isoliquiritigenin): Modulate Nrf2/GPX4 against ferroptosis; inhibit MAPKs.

• Others (dihydromyricetin, anthocyanins): Activate SIRT3; inhibit IL‑17 to reduce fibrosis.

Terpenoids (isoprene‑based) regulate gut microbiota, non‑coding RNAs, and ferroptosis.

• Monoterpenes (paeoniflorin): Resist ferroptosis via gut microbiota.

• Sesquiterpenes (artemisinin, β‑caryophyllene): Modulate AGE‑RAGE/HMGB1; activate CB2 receptors.

• Triterpenes (astragaloside IV, ginsenoside Rg3): Suppress ferroptosis; activate PPAR‑γ/adiponectin.

Phenylpropanoids (C6‑C3) target inflammation, apoptosis, and ER stress.

• Phenylpropanic acids (ferulic acid): Modulate ER‑mitochondria crosstalk.

• Lignans (schisandrin B): Target MyD88 to inhibit inflammation.

• Derivatives (salvianolic acid B): Promote Smad7 deubiquitination to reduce fibrosis.

Alkaloids (nitrogen‑containing) have well‑elucidated mechanisms.

• Berberine: Modulates SIRT3‑dependent lipophagy; suppresses NLRP3 pyroptosis.

Polysaccharides target mitochondrial dysfunction and hypertrophy.

• Lentinan: Alleviates mitochondrial dysfunction.

• Astragalus polysaccharide: Inhibits hypertrophy.

Others (curcumin, resveratrol, gastrodin):

• Curcumin activates Sirt1‑Foxo1, PI3K‑Akt, and Nrf2/HO‑1.

• Resveratrol acts through SIRT1/PGC‑1α and AMPK/mTOR.

• Gastrodin inhibits KLK8‑PAR1 and activates Nrf2.

Future Directions and Limitations

Current evidence is mainly from in vitro and rodent models. Primary targets for many compounds are unclear. Pharmacokinetic and long‑term safety data are lacking. Future research should prioritise large‑animal validation and clinical trials, exploring combinations with conventional drugs.

Conclusions

Flavonoids are the most studied, followed by terpenoids. Natural products exert effects through common pathways (oxidative stress, inflammation) and specific interventions (cell death, mitochondrial function, fibrosis). They offer a rich resource for DCM drug discovery, but further validation is urgently needed.

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https://www.xiahepublishing.com/2572-5505/JERP-2025-00063

The study was recently published in the Journal of Exploratory Research in Pharmacology.

Journal of Exploratory Research in Pharmacology (JERP) publishes original innovative exploratory research articles, state-of-the-art reviews, editorials, short communications that focus on novel findings and the most recent advances in basic and clinical pharmacology, covering topics from drug research, drug development, clinical trials and application.

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