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Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review)

  • Authors:
    • Yushu Huang
    • Xueqing Xia
    • Jingyang Xu
    • Zihan Wang
    • Yanting You
    • Qingfeng Du
  • View Affiliations / Copyright

    Affiliations: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
    Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 299
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    Published online on: August 27, 2025
       https://doi.org/10.3892/mmr.2025.13664
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Abstract

Non‑alcoholic fatty liver disease (NAFLD), characterized by excessive lipid accumulation in hepatocytes, has emerged as the leading cause of chronic liver disorders globally. As the central metabolic organ, the liver critically depends on mitochondrial integrity. Mitophagy, a selective form of autophagy, plays a pivotal role in sustaining mitochondrial homeostasis by eliminating dysfunctional mitochondria. Dysregulated mitophagy contributes to the progression of NAFLD, while its restoration mitigates disease severity. The present review outlines the tripartite axis of mitophagy, namely, the PTEN‑induced putative kinase 1/Parkin, PI3K/AKT/mTOR and AMP‑activated protein kinase pathways, in NAFLD pathogenesis across the various stages of disease development, including steatosis, nonalcoholic steatohepatitis and fibrosis, and explores their therapeutic potential. Additionally, emerging regulators, including FUN14 domain‑containing protein 1, prohibitin 2, ceramide signaling and non‑coding RNAs, which fine‑tune mitophagy in NAFLD are highlighted. By integrating evidence from pharmacological and natural agents, including traditional Chinese medicines, mitophagy‑centric strategies to promote hepatic lipid metabolism, mitigate disease progression and inform novel NAFLD therapeutics are discussed. This exploration of the mechanisms that govern mitochondrial‑autophagic crosstalk not only advances mechanistic insights but also opens new avenues for precision medicine in the treatment of metabolic liver diseases.
View Figures

Figure 1

Molecular mechanism of PINK1/Parkin
pathway-mediated mitophagy in NAFLD. Mitochondrial-localized PINK1
senses depolarized mitochondria, and Parkin, an E3 ubiquitin
ligase, participates in the mitophagy process. In the context of
NAFLD, perturbations in the PINK1/Parkin pathway impede mitophagy.
This triggers a series of downstream events, including the
activation of inflammasomes, the formation of apoptotic bodies and
the activation of hepatic stellate cells. The subsequent
morphological and functional changes of mitochondria and the
downstream pathological consequences, collectively demonstrate how
the dysregulation of PINK1/Parkin-mediated mitophagy contributes to
the progression of NAFLD. This figure was created using Biorender
software (https://app.biorender.com/). PINK1,
PTEN-induced putative kinase 1; NAFLD, non-alcoholic fatty liver
disease; mtROS, mitochondrial reactive oxygen species; ΔΨm,
mitochondrial membrane potential; LC3-II, membrane-bound
microtubule-associated protein 3; p62/SQSTM1, sequestosome 1; Ub,
ubiquitin.

Figure 2

Molecular mechanism of PI3K/AKT/mTOR
and AMPK pathway-mediated mitophagy in NAFLD. In the development of
NAFLD, the PI3K/AKT/mTOR and AMPK signaling pathways are perturbed
and ROS levels are elevated due to a high-fat diet and insulin
resistance. The PI3K/AKT pathway activates mTOR, while AMPK
responds to AMP/ATP changes to influence mTOR. Dysregulated mTOR
impacts ULK1/Atg13 and TFEB, disrupting phagophore formation and
mitophagy. Impaired mitophagy triggers inflammasome activation,
apoptotic bodies and hepatic stellate cell activation, exacerbating
NAFLD progression. This figure was created using Biorender software
(https://app.biorender.com/). AMPK,
AMP-activated protein kinase; NAFLD, non-alcoholic fatty liver
disease; ROS, reactive oxygen species; ULK1, Unc-51 like autophagy
activating kinase 1; Atg13, autophagy-related protein 13; TFEB,
transcription factor EB; LC3, microtubule-associated protein 3;
ATG, autophagy-related genes; P, phosphorylation.

Figure 3

Therapeutic interventions for NAFLD
based on mitophagy. An outline of therapeutic strategies for NAFLD
that target mitophagy to slow disease progression. The four types
of interventions are plant monomers and natural compounds,
traditional Chinese medicine, synthetic drugs and biological
molecules. These approaches aim to activate mitophagy, a key
process for clearing damaged mitochondria, ultimately delaying the
advancement of NAFLD. This figure was created using Biorender
software (https://app.biorender.com/). NAFLD,
non-alcoholic fatty liver disease.

Figure 4

Graphical abstract summarizing the
mechanism of mitophagy in NAFLD. ROS and cytokine production, lipid
peroxidation and cell death contribute to mitophagy in NAFLD. The
PINK1/Parkin, PI3K/AKT/mTOR and AMPK pathways are the main
signaling pathways involved in the regulation of mitophagy. This
figure was created using Biorender software (https://app.biorender.com/). NAFLD, non-alcoholic
fatty liver disease; ROS, reactive oxygen species; PINK1,
PTEN-induced putative kinase 1; AMPK, AMP-activated protein kinase;
UQCRC2, ubiquinol-cytochrome c reductase core protein 2; P,
phosphorylation.
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Copy and paste a formatted citation
Spandidos Publications style
Huang Y, Xia X, Xu J, Wang Z, You Y and Du Q: Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review). Mol Med Rep 32: 299, 2025.
APA
Huang, Y., Xia, X., Xu, J., Wang, Z., You, Y., & Du, Q. (2025). Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review). Molecular Medicine Reports, 32, 299. https://doi.org/10.3892/mmr.2025.13664
MLA
Huang, Y., Xia, X., Xu, J., Wang, Z., You, Y., Du, Q."Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review)". Molecular Medicine Reports 32.5 (2025): 299.
Chicago
Huang, Y., Xia, X., Xu, J., Wang, Z., You, Y., Du, Q."Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review)". Molecular Medicine Reports 32, no. 5 (2025): 299. https://doi.org/10.3892/mmr.2025.13664
Copy and paste a formatted citation
x
Spandidos Publications style
Huang Y, Xia X, Xu J, Wang Z, You Y and Du Q: Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review). Mol Med Rep 32: 299, 2025.
APA
Huang, Y., Xia, X., Xu, J., Wang, Z., You, Y., & Du, Q. (2025). Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review). Molecular Medicine Reports, 32, 299. https://doi.org/10.3892/mmr.2025.13664
MLA
Huang, Y., Xia, X., Xu, J., Wang, Z., You, Y., Du, Q."Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review)". Molecular Medicine Reports 32.5 (2025): 299.
Chicago
Huang, Y., Xia, X., Xu, J., Wang, Z., You, Y., Du, Q."Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review)". Molecular Medicine Reports 32, no. 5 (2025): 299. https://doi.org/10.3892/mmr.2025.13664
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