Lipophagy emerges as a promising target for metabolic and oxidative stress-related diseases

A review published in Genes & Diseases highlights lipophagy, the cellular process that selectively breaks down lipid droplets, as a potentially important therapeutic target for conditions driven by disrupted lipid metabolism and oxidative stress. The article brings together current understanding of how this cellular recycling mechanism maintains metabolic balance and how its disruption may contribute to a broad range of diseases.

Lipid droplets were once viewed primarily as passive stores of fat, but they are now recognized as dynamic structures involved in energy supply, cellular signaling and metabolic regulation. Through lipophagy, cells transport lipid droplets to lysosomes for degradation, releasing fatty acids that can be used for energy. This process helps prevent excessive lipid accumulation, lipotoxicity and the production of damaging reactive oxygen species (ROS).

When lipophagy is impaired, excess lipids can accumulate within cells and overwhelm mitochondria, increasing oxidative stress, inflammation and tissue damage. Disrupted lipophagy has been linked to obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), atherosclerosis, neurodegenerative diseases and kidney disorders. Lipophagy also has a complex relationship with cancer, where its effects may vary according to tumor type and metabolic requirements.

Several molecular pathways play central roles in controlling lipophagy. These include AMPK, mTORC1, ULK1, TFEB and PPARs, which respond to nutrient availability and cellular energy demands. By regulating the breakdown and use of stored lipids, these pathways help cells adapt to metabolic changes while limiting harmful lipid accumulation and oxidative damage.

The article also highlights compounds capable of influencing lipophagy, including fenofibrate, sulforaphane, hyperoside and geniposide. These compounds act through different molecular mechanisms and have demonstrated potentially beneficial effects in experimental models involving fatty liver disease, obesity and atherosclerosis.

Despite its therapeutic promise, manipulating lipophagy requires careful control. Excessive breakdown of lipid droplets could release large amounts of free fatty acids, potentially increasing mitochondrial stress and producing unintended effects. Tissue-specific regulation, precise targeting and a clearer understanding of the pathway’s complex biological interactions will therefore be important before lipophagy-based approaches can advance clinically.

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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Reference

Qingqing Zhao, Fei Qu, Yi Jin, Lipophagy: A key regulator in oxidative stress and metabolic disorders, Genes & Diseases, Volume 13, Issue 6, 2026, 102049, https://doi.org/10.1016/j.gendis.2026.102049

Funding

National Natural Science Foundation of China 82401009

Shandong Provincial Natural Science Foundation (China) ZR2025MS1456

Research Start-up Fee for Introducing Talents to Jinan Central Hospital (China) YJRC2023001