2. Academic Validation
  3. FGF21-FGFR1 signaling protects against cardiac hypertrophy by regulating PINK1-mediated mitophagy pathway

FGF21-FGFR1 signaling protects against cardiac hypertrophy by regulating PINK1-mediated mitophagy pathway

  • J Adv Res. 2025 Oct 29:S2090-1232(25)00848-3. doi: 10.1016/j.jare.2025.10.053.
Lei Chen 1,  Lingxin Zheng 2,  Yuan Qin 3,  Bilin Liu 3,  Yejing Zheng 4,  Xiaojian Tong 4,  Mengting Dai 4,  Guohua Gong 5
Affiliations

Affiliations

  • 1 Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Department of Blood Transfusion, The First Affiliated Hospital (Southwest Hospital) of Army Medical University, Chongqing 400038, China.
  • 2 The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 4 Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 5 Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: guohgong@wmu.edu.cn.
PMID: 41173187 DOI: 10.1016/j.jare.2025.10.053
Abstract

Introduction: Cardiac hypertrophy is an independent risk factor and the primary predictor of heart failure (HF). Mitochondria are crucial for the shift from hypertrophy to heart failure. The expression of Fibroblast Growth Factor 21 (FGF21), a cardioprotective factor, is increased in patients with cardiac hypertrophy but fails to prevent heart failure. Additionally, the molecular mechanism through which FGF21 exerts its beneficial effects on hypertrophic myocardial mitochondria remains unclear.

Objectives: Our study investigated the effect of FGF21 on cardiac hypertrophy, elucidating its mechanism of action through the enhancement of mitophagy-mediated cardioprotection.

Methods: A transverse aortic constriction (TAC) model and a phenylephrine (PE) model were applied to explore the effect and mechanism of FGF21. P62-mediated Mitophagy inducer (PMI) and rapamycin (Rapa) were used to confirm that FGF21-regulated Mitophagy under overload pressure conditions.

Results: FGF21 knockout markedly exacerbated TAC-induced cardiac function damage, mitochondrial damage, and Mitophagy impairment. In vitro, FGF21 knockdown aggravated PE-induced cardiomyocyte hypertrophy and Mitophagy dysfunction. FGF21 treatment promoted Mitophagy in the TAC and PE models, but this effect was abolished in the absence of PTEN-induced putative kinase 1 (PINK1). The increase in PINK1 expression induced by Rapa can rescue impaired cardiac function and Mitophagy impairment in FGF21-deficient TAC mice. Similarly, PMI enhances Mitophagy, which inhibits damage to cardiac functions. A further study revealed that the expression of Fibroblast Growth Factor receptor 1 (FGFR1) and FGF21 was opposite in heart failure. Knockdown of FGFR1 inhibited FGF21-mediated Mitophagy.

Conclusion: FGF21 promotes PINK1-mediated Mitophagy to attenuate cardiac hypertrophy, and mismatched FGFR1 expression may hamper the beneficial effect of FGF21 on cardiac hypertrophy.

Keywords

Cardiac hypertrophy; FGF21; FGFR1; Mitophagy; PINK1.

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