Autophagy-lysosome pathway dysfunction in MASLD progression: molecular mechanisms and therapeutic targets.
5 affiliations
- 1The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China.
- 2Medical College, Henan University of Chinese Medicine, Zhengzhou, China.
- 3Henan Medical College, Zhengzhou, China.
- 4The First Affiliated Hospital of Henan University of TCM, Zhengzhou, China.
- 5The Second Affiliated Hospital of Henan University of TCM, Zhengzhou, China.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, yet no standardized pharmacotherapy has been approved for clinical use. The autophagy-lysosome pathway (ALP) serves as an essential intracellular degradation and recycling machinery that sustains hepatic metabolic homeostasis via modulation of lipid turnover, mitochondrial quality surveillance, and hepatocellular detoxification. Accumulating evidence demonstrates that ALP impairment acts as a core pathogenic factor across all stages of MASLD progression. This review systematically elaborates the molecular framework of the ALP and its multifaceted physiological functions in the liver, with special attention to the central pathogenic mechanisms underlying ALP impairment in MASLD: lysosomal dysfunction, defective autophagosome-lysosome fusion, dysregulation of key transcriptional and epigenetic regulators, and impaired subtypes of selective autophagy. ALP activity displays stage-specific characteristics across MASLD progression, featuring compensatory activation in simple hepatic steatosis but functional suppression in metabolic dysfunction-associated steatohepatitis (MASH). Hepatocytes and hepatic stellate cells exert opposing autophagic activity during liver fibrogenesis. We further summarize existing therapeutic strategies targeting the ALP, which fall into three categories: pharmacological agents (ALP agonists, lysosomal modulators, natural bioactive compounds, and nano-drug delivery systems), non-pharmacological interventions (dietary adjustment, physical exercise, and lifestyle modification), and gut-liver axis regulatory approaches. Finally, we address the primary translational bottlenecks and prospective avenues for converting these mechanistic findings into viable clinical therapies.
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BibTeX
@article{cao2026autophagylysosome,
title = {{Autophagy-lysosome pathway dysfunction in MASLD progression: molecular mechanisms and therapeutic targets.}},
author = {Shuaibing Cao and Xinyue Cheng and Yi Yang and Baoping Lu and Shan Li and Chuntian Huang and Mingyu Ba and Lei Luo and Changpu Zhao},
journal = {Frontiers in medicine},
year = {2026},
month = oct,
doi = {10.3389/fmed.2026.1961366},
url = {https://europepmc.org/article/MED/42953075},
note = {CC BY},
}
RIS
TY - JOUR
TI - Autophagy-lysosome pathway dysfunction in MASLD progression: molecular mechanisms and therapeutic targets.
AU - Shuaibing Cao
AU - Xinyue Cheng
AU - Yi Yang
AU - Baoping Lu
AU - Shan Li
AU - Chuntian Huang
AU - Mingyu Ba
AU - Lei Luo
AU - Changpu Zhao
PY - 2026
DA - 2026/10/14
JO - Frontiers in medicine
DO - 10.3389/fmed.2026.1961366
UR - https://europepmc.org/article/MED/42953075
AB - Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, yet no standardized pharmacotherapy has been approved for clinical use. The autophagy-lysosome pathway (ALP) serves as an essential intracellular degradation and recycling machinery that sustains hepatic metabolic homeostasis via modulation of lipid turnover, mitochondrial quality surveillance, and hepatocellular detoxification. Accumulating evidence demonstrates that ALP impairment acts as a core pathogenic factor across all stages of MASLD progression. This review systematically elaborates the molecular framework of the ALP and its multifaceted physiological functions in the liver, with special attention to the central pathogenic mechanisms underlying ALP impairment in MASLD: lysosomal dysfunction, defective autophagosome-lysosome fusion, dysregulation of key transcriptional and epigenetic regulators, and impaired subtypes of selective autophagy. ALP activity displays stage-specific characteristics across MASLD progression, featuring compensatory activation in simple hepatic steatosis but functional suppression in metabolic dysfunction-associated steatohepatitis (MASH). Hepatocytes and hepatic stellate cells exert opposing autophagic activity during liver fibrogenesis. We further summarize existing therapeutic strategies targeting the ALP, which fall into three categories: pharmacological agents (ALP agonists, lysosomal modulators, natural bioactive compounds, and nano-drug delivery systems), non-pharmacological interventions (dietary adjustment, physical exercise, and lifestyle modification), and gut-liver axis regulatory approaches. Finally, we address the primary translational bottlenecks and prospective avenues for converting these mechanistic findings into viable clinical therapies.
SN - 2296-858X
ER -