Formononetin mediates the protective effect on diabetic cardiomyopathy through PPARγ-regulated ferroptosis suppression

Q: What are the key findings of this study?

Formononetin, a bioactive constituent of Gegen Qinlian capsule with high PPARgamma binding affinity (-9.3 kcal/mol), attenuated diabetic cardiomyopathy by suppressing ferroptosis via PPARgamma.

Q: What is the clinical evidence from this study?

Population: Diabetic cardiomyopathy (murine and cellular models) (n=45). Intervention: Gegen Qinlian capsule (GGQL) and Formononetin (FMN) vs. Distilled water or 0.5% CMC-Na vehicle control (with or without GW9662 1 mg/kg/day). Primary outcome: Cardiac injury (LVEF, LVFS, hypertrophy, fibrosis) and ferroptosis suppression via PPARgamma-PI3K/AKT/mTOR-GPX4/SLC7A11 axis (p=<0.05).

Q: What does this research mean for the field?

Formononetin, a bioactive constituent of Gegen Qinlian capsule, attenuates diabetic cardiomyopathy by suppressing cardiomyocyte ferroptosis through a PPARγ-PI3K/AKT/mTOR-GPX4/SLC7A11 signaling pathway. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To investigate the therapeutic mechanism of Gegen Qinlian capsule in diabetic cardiomyopathy and identify the candidate bioactive constituent responsible for cardioprotection.

Rui Yao; Huimin Xiao; Yiheng Quan; 刘彬彬; Siwang Wang; Jinming Gao

doi:10.1007/s10565-026-10303-y

October 31, 2026Cell Biology and ToxicologyOpen Access

Formononetin mediates the protective effect on diabetic cardiomyopathy through PPARγ-regulated ferroptosis suppression

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Key result

Formononetin attenuates diabetic cardiomyopathy by suppressing ferroptosis via PPARgamma activation.

P<0.05
n=45

Why the study?

The therapeutic mechanism of Gegen Qinlian capsule in diabetic cardiomyopathy and its key candidate bioactive constituent responsible for cardioprotection needed to be identified.

Does formononetin (a bioactive constituent of Gegen Qinlian capsule) attenuate diabetic cardiomyopathy and suppress ferroptosis via PPARγ signaling in murine and cellular models of diabetic cardiomyopathy?

Key Points

To investigate the therapeutic mechanism of Gegen Qinlian capsule in diabetic cardiomyopathy and identify the candidate bioactive constituent responsible for cardioprotection.
Established a murine diabetic cardiomyopathy model in male C57BL/6J mice using high-fat diet feeding combined with streptozotocin injection (100 mg/kg), followed by 8 weeks of Gegen Qinlian capsule administration across three doses.
Profiled transcriptional and metabolic reprogramming using RNA sequencing, untargeted metabolomics, network pharmacology, molecular docking, and cellular thermal shift assay.
Assessed ferroptosis markers and validated target pathways using lentiviral PPARG knockdown in H9C2 cardiomyocytes and pharmacological PPARγ inhibition with GW9662 in vivo.
Gegen Qinlian capsule dose-dependently attenuated cardiomyocyte hypertrophy, myocardial fibrosis, and systolic dysfunction while suppressing ferroptotic markers (MDA, ROS, Fe2+) and restoring GPX4 and SLC7A11 expression.
Network pharmacology and docking identified formononetin as the primary active compound with high PPARγ binding affinity (-9.3 kcal/mol), confirmed by direct cellular target engagement in cellular thermal shift assays.
PPARG silencing or GW9662 co-administration abolished formononetin-mediated cardioprotection and anti-ferroptotic activity, whereas downstream PI3K inhibition reversed formononetin-induced GPX4 and SLC7A11 upregulation.

Structured PICO

Does formononetin (a bioactive constituent of Gegen Qinlian capsule) attenuate diabetic cardiomyopathy and suppress ferroptosis via PPARγ signaling in murine and cellular models of diabetic cardiomyopathy?

P

Population

45 male C57BL/6J mice (8 weeks old) with high-fat diet and streptozotocin-induced diabetic cardiomyopathy (fasting blood glucose >= 11.1 mmol/L), treated for 8 weeks, alongside H9C2 rat cardiomyocytes and primary neonatal rat ventricular myocytes.

I

Intervention

In vivo Cohort 1: Gegen Qinlian Decoction (GGQL) extract suspended in distilled water administered daily by oral gavage at low (227.5 mg/kg/day), medium (445 mg/kg/day), or high (910 mg/kg/day) doses for 8 weeks on a background of high-fat diet maintenance. In vivo Cohort 2: Formononetin (FMN) 10 mg/kg/day suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) by oral gavage once daily, with or without the PPARγ antagonist GW9662 (1 mg/kg/day dissolved in saline, intraperitoneal injection once daily) for 8 weeks. In vitro: FMN (1, 5, and 10 µM) or ferrostatin-1 (1 µM) co-administered during 24-hour high-glucose/high-fat challenge.

C

Comparator

In vivo Cohort 1: Normal control and DbCM model control mice receiving equivalent volumes of distilled water by oral gavage daily for 8 weeks. In vivo Cohort 2: DbCM vehicle control receiving 0.5% CMC-Na solution by oral gavage once daily plus saline by intraperitoneal injection once daily, and DbCM + GW9662 (1 mg/kg/day IP) alone, all maintained on background high-fat diet. In vitro: Untreated controls, DMSO vehicle controls (≤ 0.1%), scrambled shRNA control (sh-NC), and empty vector control (OE-NC).

O

Outcome

Cardiac function and structural injury at 8 weeks (echocardiographic LVEF, LVFS, LVEDd, LVESd; cardiomyocyte cross-sectional area via HE and WGA staining; myocardial fibrotic area fraction via Masson's trichrome staining; serum CK-MB and LDH) and ferroptosis/signaling markers (GPX4, SLC7A11, PPARγ, CPT-1β, ACSL4, PI3K/AKT/mTOR protein expression, MDA, SOD, ROS, lipid ROS, Fe2+, and GSH/GSSG ratio).surrogate

Main Result

p-value: p=<0.05

This preclinical study identifies formononetin as a key bioactive component of Gegen Qinlian capsule that protects against diabetic cardiomyopathy by activating PPARγ-PI3K/AKT/mTOR signaling to inhibit cardiomyocyte ferroptosis.

Implication

Should not yet change diabetic cardiomyopathy management; leaves open whether PPARγ-mediated ferroptosis suppression translates to humans.

Abstract

To investigate the therapeutic mechanism of Gegen Qinlian capsule (GGQL) in diabetic cardiomyopathy (DbCM) and identify a key candidate bioactive constituent responsible for cardioprotection. A murine DbCM model was established by high-fat diet feeding combined with streptozotocin injection. GGQL was administered at three doses for 8 weeks. Cardiac injury was evaluated by echocardiography, histology, and serum biomarkers. Untargeted metabolomics and RNA sequencing were performed to characterize metabolic and transcriptional reprogramming. Network pharmacology, molecular docking, and cellular thermal shift assay (CETSA) were integrated to identify the principal active compound and its molecular target. Ferroptosis was assessed through GPX4/SLC7A11 protein expression, oxidative stress markers (MDA, ROS, Fe 2+ ), and antioxidant capacity. Mechanistic validation employed PPARG lentiviral knockdown in H9C2 cardiomyocytes and pharmacological PPARγ antagonism (GW9662) in vivo. GGQL dose-dependently attenuated cardiomyocyte hypertrophy, myocardial fibrosis, and systolic dysfunction, while suppressing ferroptotic markers and restoring GPX4/SLC7A11 expression. Multi-omics profiling converged on PPAR signaling and fatty acid oxidation as dominant therapeutic axes. Network pharmacology identified PPARγ as the central hub target. Formononetin (FMN) exhibited the highest PPARγ binding affinity (-9.3 kcal/mol), and CETSA confirmed direct intracellular target engagement. PPARG silencing and GW9662 co-administration each abolished FMN-mediated cardioprotection and anti-ferroptotic effects. Mechanistically, FMN activated the PI3K/AKT/mTOR signaling axis downstream of PPARγ, and PI3K inhibition reversed GPX4/SLC7A11 upregulation. FMN is a key candidate bioactive constituent of GGQL that attenuates DbCM by suppressing ferroptosis through a PPARγ-PI3K/AKT/mTOR-GPX4/SLC7A11 signaling cascade, providing a mechanistic basis for GGQL's clinical use in diabetic cardiovascular disease.

Discussion

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Cite This Study

Yao et al. (2026) studied Diabetic cardiomyopathy (murine and cellular models) (n=45). Gegen Qinlian capsule (GGQL) and Formononetin (FMN) vs. Distilled water or 0.5% CMC-Na vehicle control (with or without GW9662 1 mg/kg/day) was evaluated on Cardiac injury (LVEF, LVFS, hypertrophy, fibrosis) and ferroptosis suppression via PPARgamma-PI3K/AKT/mTOR-GPX4/SLC7A11 axis (p=<0.05). Formononetin, a bioactive constituent of Gegen Qinlian capsule with high PPARgamma binding affinity (-9.3 kcal/mol), attenuated diabetic cardiomyopathy by suppressing ferroptosis via PPARgamma.

synapsesocial.com/papers/6ae7d421edffb496294104b9 https://doi.org/10.1007/s10565-026-10303-y

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Formononetin mediates the protective effect on diabetic cardiomyopathy through PPARγ-regulated ferroptosis suppression

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

Formononetin mediates the protective effect on diabetic cardiomyopathy through PPARγ-regulated ferroptosis suppression

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

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