LGR6 couples maresin 1 signaling to glycolytic flux and protein lactylation for the rescue of diabetic cardiomyopathy

Q: What are the key findings of this study?

Maresin 1 significantly improved cardiac diastolic function (E/A ratio 1.25 vs 0.84 in vehicle) and attenuated pathological hypertrophy and fibrosis in db/db mice by restoring metabolic flexibility and mitophagy via LGR6 signaling.

Q: What is the clinical evidence from this study?

Population: Diabetic cardiomyopathy (DbCM) (n=24). Intervention: Maresin 1 (MaR1) vs. Vehicle. Primary outcome: Diastolic function (E/A ratio) (p=<0.01).

Q: What does this research mean for the field?

Maresin 1 protects against diabetic cardiomyopathy by signaling through LGR6 to restore metabolic flexibility, protein lactylation, and mitophagy. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

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

To determine whether the specialized pro-resolving lipid mediator maresin 1 reverses metabolic-epigenetic defects and restores mitochondrial quality control in diabetic cardiomyopathy through the receptor LGR6.

Bin Feng; Chao Chen; Lin Chen; Yuqiong Chen; Wenjun Mao; Peiran Yu; Hao Yu; 施毕旻; Nannan Zhang

doi:10.1111/jdi.70464

October 7, 2026Journal of Diabetes InvestigationOpen Access

LGR6 couples maresin 1 signaling to glycolytic flux and protein lactylation for the rescue of diabetic cardiomyopathy

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Key result

Maresin 1 improves diabetic diastolic function, boosting E/A ratio to ~1.25 via LGR6 signaling.

P<0.01
n=24

Why the study?

Diabetic cardiomyopathy is driven by metabolic inflexibility and impaired mitochondrial clearance, and the capacity of Maresin 1 to correct these metabolic-epigenetic disturbances remains undefined.

Does Maresin 1 (MaR1) improve cardiac function and mitigate pathological remodeling in preclinical models of diabetic cardiomyopathy?

Key Points

To determine whether the specialized pro-resolving lipid mediator maresin 1 reverses metabolic-epigenetic defects and restores mitochondrial quality control in diabetic cardiomyopathy through the receptor LGR6.
Treated male db/db diabetic mice and palmitic acid-stimulated H9c2 cardiomyocytes with vehicle or maresin 1 (3 ng and 10 ng doses) over a 22-week study period.
Evaluated myocardial function and structure via echocardiography, histology (H&E, WGA, and Masson's trichrome), and transmission electron microscopy.
Assessed metabolic enzymes, protein lactylation, and mitophagy signaling via immunoblotting, qPCR, and immunohistochemistry following siRNA knockdown of LGR6.
MaR1 administration reduced glucose intolerance by ~25% in IPGTT AUC and significantly restored diastolic function in db/db mice, improving E/A from 0.84 ± 0.16 to 1.25 ± 0.18 (10 ng, P < 0.01) and lowering IVRT from 24.26 ± 3.51 ms to 19.19 ± 3.26 ms (10 ng, P < 0.01).
MaR1 reactivated myocardial AMPK signaling, restored rate-limiting enzymes (CPT1B, PFK-1, HK2), elevated intracellular lactate, rescued global protein lysine lactylation, and re-established PINK1/Parkin-mediated mitophagy.
In vitro knockdown of the receptor LGR6 completely abolished MaR1-induced glycolytic activation, lysine lactylation restoration, and mitophagic clearance.

Structured PICO

Does Maresin 1 (MaR1) improve cardiac function and mitigate pathological remodeling in preclinical models of diabetic cardiomyopathy?

P

Population

24 male mice (18 diabetic db/db and 6 nondiabetic db/m controls) starting at 6 weeks of age were followed for 22 weeks to study the effects of Maresin 1 on diabetic cardiomyopathy.

I

Intervention

Maresin 1 (MaR1) administered via daily intraperitoneal injection (3 ng/mouse or 10 ng/mouse) for 22 weeks (in vivo); MaR1 (20 nM or 50 nM) applied prior to palmitic acid exposure (in vitro).

C

Comparator

Vehicle-treated db/db mice and vehicle-treated db/m controls (in vivo); BSA vehicle or palmitic acid alone (in vitro).

O

Outcome

Cardiac diastolic function, pathological hypertrophy, interstitial fibrosis, and molecular markers of oxidative stress, inflammation, and mitophagy.surrogate

Main Result

Absolute Event Rate: 1.25% vs 0.84%

p-value: p=<0.01

Maresin 1 protects against diabetic cardiomyopathy in preclinical models by activating LGR6-dependent metabolic-epigenetic reprogramming, increasing lactylation, and restoring mitochondrial quality control.

Limitations

The precise histone and non-histone targets of lysine lactylation in diabetic cardiomyocytes remain to be fully mapped.
The study does not prove that AMPK activation, p300 upregulation, or PINK1/Parkin-associated mitophagy are direct downstream events of LGR6 signaling rather than secondary effects.
Systemic administration of MaR1 significantly improved glucose tolerance, meaning reduced systemic metabolic stress may contribute to the observed cardiac improvement.
Macrophage infiltration and macrophage-specific LGR6 signaling were not directly assessed in vivo.

Implication

Preclinical data position MaR1 as a candidate for diabetic cardiomyopathy; leaves open clinical translation of LGR6-dependent effects.

Abstract

Background Diabetic cardiomyopathy (DbCM) is driven by metabolic inflexibility and impaired mitochondrial clearance. While the pro‐resolving lipid mediator Maresin 1 (MaR1) shows therapeutic promise, its capacity to correct the underlying metabolic‐epigenetic disturbances in DbCM remains undefined. Materials Db/db mice and palmitic acid (PA)‐exposed H9c2 cardiomyocytes were treated with MaR1. Cardiac function and structure were assessed by echocardiography and histological analysis. Myocardial oxidative stress, inflammation, and key molecular pathways were evaluated via immunoblotting, qPCR, immunohistochemistry, and transmission electron microscopy. The role of the putative receptor LGR6 was investigated using siRNA‐mediated knockdown. Results MaR1 improved cardiac diastolic function, attenuated pathological hypertrophy and interstitial fibrosis, and reduced oxidative stress and inflammatory markers in db/db mice. Mechanistically, MaR1 activated AMPK signaling, restoring the expression of crucial enzymes for both fatty acid oxidation (CPT1B) and glycolysis (PFK‐1, HK2). This metabolic reprogramming elevated intracellular lactate, which in turn replenished the deficient global protein lysine lactylation (Kla). Concurrently, MaR1 reactivated the PINK1/Parkin pathway, restoring mitophagy‐associated signaling. In vitro, exogenous lactate supplementation recapitulated these effects. Importantly, LGR6 silencing abrogated all MaR1‐induced benefits, including glycolytic activation, lactylation rescue, and mitophagic recovery. Conclusion MaR1 protects against DbCM by signaling through LGR6 to restore metabolic flexibility, thereby fueling a lactate‐dependent lactylation program that is critically associated with the reactivation of mitochondrial quality control via mitophagy. This study unveils a critical metabolic‐epigenetic axis as a novel therapeutic target.

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Cite This Study

Feng et al. (2026) studied Diabetic cardiomyopathy (DbCM) (n=24). Maresin 1 (MaR1) vs. Vehicle was evaluated on Diastolic function (E/A ratio) (p=<0.01). Maresin 1 significantly improved cardiac diastolic function (E/A ratio 1.25 vs 0.84 in vehicle) and attenuated pathological hypertrophy and fibrosis in db/db mice by restoring metabolic flexibility and mitophagy via LGR6 signaling.

synapsesocial.com/papers/6ac835407c3139e1cb0e7dc5 https://doi.org/10.1111/jdi.70464

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LGR6 couples maresin 1 signaling to glycolytic flux and protein lactylation for the rescue of diabetic cardiomyopathy

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

LGR6 couples maresin 1 signaling to glycolytic flux and protein lactylation for the rescue of diabetic cardiomyopathy

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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