Open research questions in Autophagy in Disease and Therapy

What the literature leaves open

• The current treatment modalities for HCC have substantial limitations. There is a need to re-evaluate therapeutic strategies in light of the epidemiological shift from infection-driven to metabolically driven disease. The role of phytochemicals in modulating PI3K/Akt/mTOR-driven autophagy in liver cancer is not well understood.

  Modulating PI3K/Akt/mTOR-driven autophagy in liver cancer. The role of phytochemicals · 2026 · DOI

• The molecular mechanisms of autophagy's role in seed development are not fully understood. The interaction between autophagy and ABA signaling in seed germination is not well characterized.

  Autophagy-related genes AtATG5 and AtATG7 influence reserve mobilization and ABA responses during Arabidopsis seed germination · 2026 · DOI

• The gap is the lack of understanding of the mechanisms responsible for RPE alterations. The paper identifies the need to investigate the role of autophagy and mTOR in RPE degeneration.

  Neuronal death and accumulation of lipid droplets and glycogen granules within retinal pigment epithelium under the influence of mTOR and autophagy · 2026 · DOI

• Need for targeted delivery of therapeutic agents to tumor cells. Complexity of mitophagy regulation and its role in tumor progression.

  Scutellarein nanoparticles suppress colon cancer via PHB2-mediated mitophagy inhibition with modulatory effects on tumor-associated depression and osteotropic migration · 2026 · DOI

• There are no effective treatments available for diabetic neuropathy. The mechanisms of cell death involved in diabetic neuropathy are not fully understood.

  Different Types of Cell Death in Diabetic Neuropathy: A Focus on Mechanisms and Therapeutic Strategies · 2024 · DOI

• However, the role of VPS4B in osteogenic and adipogenic differentiation from mesenchymal stem/progenitor cells remains to be explored.

  Vacuolar protein sorting 4B is a novel regulator of osteoblast and adipocyte differentiation by activating autophagy signaling · 2026 · DOI

• Lysosomes are a major organelle involved in intracellular degradation, membrane traffic and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined.

  The Lysosomal Clock: Are We Only as Old as Our Lysosomes? · 2026 · DOI

• Mitophagy plays a key role in glioma radioresistance, but its upstream regulatory mechanism is not fully understood.

  USP4‐Mediated Deubiquitination of PTBP1 Promotes Glioma Progression and Radioresistance by Enhancing PHB2‐Dependent Mitophagy · 2026 · DOI

• However, its role in lysosomal biogenesis and autophagy remains poorly understood.

  PQ-loop repeat-containing 2 (PQLC2) regulates mTORC1 lysosomal localization and autophagic flux · 2026 · DOI

• Tumor protein p53-inducible nuclear protein 2 (Tp53inp2) is known to be a positive regulator of autophagy under physiological conditions, but the mechanism of Tp53inp2 in IS remains unclear.

  Inhibition of METTL14 Alleviates OGD /R‐Induced Neuronal Differentiation Injury in Neural Stem Cells Through Suppressing the Tp53inp2/Ptgs2 Axis: Potential Benefits for the Mouse MCAO Model · 2026 · DOI

• Despite these similarities, whether TMEM41B and VMP1 exhibit different roles in very low-density lipoprotein (VLDL) secretion and autophagy in the pathogenesis of metabolic-associated steatotic liver disease (MASLD) remains unclear.

  Overlapping Yet Distinct Functions of Vacuole Membrane Protein 1 and Transmembrane Protein 41B in Modulating Hepatic Lipoprotein Secretion and Autophagy · 2026 · DOI

• However, the role of mitophagy dysregulation in dust-induced mitochondrial dysfunction and the underlying treatment with kinetin remain unclear.

  Activation of Mitophagy by Kinetin Mitigates Coal–Silica Mixed Dust-Induced Pulmonary Fibrosis via Modulating Macrophage Mitochondrial Function in Mice · 2026 · DOI

• Cerebral ischemia-reperfusion injury (CIRI) is a key contributor to stroke-related neurological damage, but the functional interplay between autophagy and ferroptosis—two critical pathological processes—remains poorly understood.

  Dual Regulation of ACSL3 by TRIM33-Mediated Ubiquitination and NBR1-Dependent Autophagy: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury · 2026 · DOI

• While mitophagy sustains mitochondrial homeostasis, how impaired autophagic flux disrupts intestinal barrier function remains unclear.

  USP26 Promotes Autophagosome–Lysosome Fusion to Improve Mitochondrial Function in the Repair of Gut Barrier Damage by Stabilizing STX17 · 2026 · DOI

• Berbamine (BBM), a natural bisbenzylisoquinoline alkaloid, has anticancer activity, but its effects on autophagy- and lysosome-related processes in breast cancer remain incompletely understood.

  Berbamine exerts anti-breast-cancer effects in association with autophagy-related responses and PI3K/Akt1/mTOR signaling · 2026 · DOI

• Previous in vitro studies showed that phagophores originate from ER membranes, but the structural relationship between phagophores and the ER membrane in vivo remains unknown.

  Phagophores originate from endoplasmic reticulum membranes in vasopressin neurons in a mouse model of familial neurohypophysial diabetes insipidus · 2025 · DOI

• However, its role in the Germline stem cell (GSC)-niche, including its effects on GSCs and niche cells, remains unexplored.

  Autophagy is dispensable in germline stem cells but is required in the cap cells for their maintenance in the Drosophila ovarian niche · 2025 · DOI

• Therefore, lysosomal damage is closely related to the pathogenesis of DKD, but effective prevention and treatment measures are still lacking.

  Melatonin attenuates kidney injury by alleviating lysosomal damage in diabetic kidney disease · 2025 · DOI

• However, the regulation of macrophage autophagy by pyruvate dehydrogenase (PDH), a key component of the PDH complex involved in energy and metabolic homeostasis, remains poorly understood in the context of atherosclerosis induced by Hcy.

  Pyruvate dehydrogenase alleviates macrophage autophagy in Hcy-induced ApoE–/– mice · 2025 · DOI

• However, it remains unclear whether β1-AA induces cardiac autophagy rhythm disorders by affecting PER2 expression.

  Reduced expression of the PER2 protein contributes to β1-AA-induced cardiac autophagy rhythm disorders · 2025 · DOI

• However, its role in colorectal cancer (CRC) progression remains poorly understood.

  ANT1 suppression inhibits the progression of colorectal cancer by suppressing PINK1/Parkin-mediated mitophagy · 2025 · DOI

• Peroxisomes, key metabolic organelles, maintain metabolic homeostasis, yet their role in immune cells remains underexplored.

  Aging impairs peroxisome biogenesis in human B cells · 2025 · DOI

• The crosstalk between clathrin-mediated endocytosis (CME) and the autophagy pathway has been reported in mammals; however, the interconnection of CME with autophagy has not been established in plants.

  Clathrin light chains negatively regulate plant immunity by hijacking the autophagy pathway · 2024 · DOI

• Investigate the long-term effects of Scu-NPs treatment on colon cancer, - Examine the efficacy of Scu-NPs in other types of cancer, - Study the potential toxicity of Scu-NPs…

  Scutellarein nanoparticles suppress colon cancer via PHB2-mediated mitophagy inhibition with modulatory effects on tumor-associated depression and osteotropic migration · 2026 · DOI

• Future research is necessary to determine which mode of cell death predominates in specific neural…

  Different Types of Cell Death in Diabetic Neuropathy: A Focus on Mechanisms and Therapeutic Strategies · 2024 · DOI

Most-cited papers in Autophagy in Disease and Therapy

• Autophagy fights disease through cellular self-digestion · Nature · 2008 · 5,704 citations
• Autophagy regulates lipid metabolism · Nature · 2009 · 3,601 citations
• Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice · Nature · 2006 · 3,389 citations
• TFEB Links Autophagy to Lysosomal Biogenesis · Science · 2011 · 3,102 citations
• Loss of autophagy in the central nervous system causes neurodegeneration in mice · Nature · 2006 · 3,073 citations
• Autophagy as a Regulated Pathway of Cellular Degradation · Science · 2000 · 3,024 citations
• Autophagy in immunity and inflammation · Nature · 2011 · 2,876 citations
• Induction of autophagy and inhibition of tumorigenesis by beclin 1 · Nature · 1999 · 2,818 citations
• The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy · Nature · 2015 · 2,674 citations
• Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 · Autophagy · 2021 · 2,622 citations

Most recent work

• Mitophagy in the pathogenesis and management of disease · Cell Research · 2026
• Lysosomes as hubs of metabolic sensing and cellular homeostasis · Molecular Cell · 2026
• Core principles of autophagy initiation mechanisms · Nature Structural & Molecular Biology · 2026
• FIG4 downregulation-arrested autophagy-lysosomal degradation of IL-18 drives lipid-associated macrophage polarization and immunotherapy resistance in triple-negative breast cancer · Cancer Letters · 2026
• A glycolytic shunt via the pentose phosphate pathway is a metabolic checkpoint for nervous system sensory homeostasis and axonal regeneration · Cell · 2026
• Links Between Autophagy and Healthy Aging · Journal of Molecular Biology · 2026
• Mitochondria-lysosome coupling contributes to lysosome acidification and aging · Molecular Cell · 2026
• AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites · Autophagy · 2026
• mTOR pathway mediates the endoplasmic reticulum stress -apoptosis of CD4+ T cell through inhibiting autophagy flux in sepsis · Inflammation Research · 2026
• New perspective on neurodegenerative diseases: Focusing on the interaction between autophagy and oxidative stress and targeted strategies · Neurobiology of Disease · 2026

Related topics in Medicine