Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles
Open accessAbstract
Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.
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Endogenous defects in autophagy are associated with embryonic lethality, developmental defects, and multiple pathological disorders including neurodegeneration, cancer, and cardiovascular disorders.
“and permanent or transient endogenous defects in autophagy have been associated with embryonic lethality, developmental defects, and multiple pathological disorders, including (but not limited to) neurodegeneration, cancer, and cardiovascular disorders [812–817].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [815]
mTOR inhibitors such as rapamycin, rapamycin analogues and mTORC1 kinase inhibitors are widely used as immunosuppressive agents in clinical settings.
“mTOR inhibitors, such as rapamycin, rapamycin analogues and mTORC1 kinase inhibitors, are already widely used as immunosuppressive agents in clinical settings18.”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [18]
The list of chemical activators of autophagy includes mTOR inhibitors and mTOR-independent agents.
“The expanding list of chemical activators of autophagy includes mTOR inhibitors and mTOR-independent agents18,29,36,192.”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [18]
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Self-citationAutophagy in acute brain injury
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Self-citationTsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationBiological Functions of Autophagy Genes: A Disease Perspective
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Self-citationChloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion
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Self-citationMolecular definitions of autophagy and related processes
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Self-citationMitochondrial metabolism and cancer
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Self-citationMitochondrial control of inflammation
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Self-citationThe Roles of Autophagy in Cancer
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Autophagy-Independent Functions of the Autophagy Machinery
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“In particular, this may have led investigators to misattribute phenotypic or functional effects caused by the pharmacological or genetic perturbation of single autophagy-regulatory factors to autophagy as a process (Galluzzi et al., 2017b) .”
BackgroundSelf-citationAutophagy and mitophagy in cardiovascular disease
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Control of Metastasis by NK Cells
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Self-citationTargeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy
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Machinery, regulation and pathophysiological implications of autophagosome maturation
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Self-citationAutophagy and inflammation in chronic respiratory disease
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Linking cellular stress responses to systemic homeostasis
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Self-citationMitochondrial Sirtuin 3: New emerging biological function and therapeutic target
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Autophagy in kidney homeostasis and disease
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The spectrum of T cell metabolism in health and disease
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Self-citationLipid Droplets in Cancer: Guardians of Fat in a Stressful World
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Autophagy, cancer stem cells and drug resistance
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Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy
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Self-citationTargeting autophagy in obesity: from pathophysiology to management
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Low temperature photothermal therapy: Advances and perspectives
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Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles
Bonora, M., Wieckowski, M. R., Sinclair, D. A., Kroemer, G., Pinton, P., & Galluzzi, L. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0074-0 · Cited by 299 · see citing works
Self-citationThe autophagic network and cancer
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Self-citationAutophagy and the hallmarks of aging
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Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics
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The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes
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WNT Signaling in Cancer Immunosurveillance
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Autophagy in Cardiovascular Aging
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Self-citationMarchi, S., Giorgi, C., Galluzzi, L., & Pinton, P. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.017 · Cited by 235 · see citing works
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Evolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process
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Autophagy in the physiological endometrium and cancer
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Bcl-2 Antiapoptotic Family Proteins and Chemoresistance in Cancer
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Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy
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Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer
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Self-citationImmunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212 · see citing works
Self-citationRegulation and function of V-ATPases in physiology and disease
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The multifaceted role of autophagy in cancer and the microenvironment
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Autophagy in aging and longevity
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NK cells and solid tumors: therapeutic potential and persisting obstacles
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Self-citationAutophagy-regulating protease Atg4: structure, function, regulation and inhibition
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- Authors
- Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R., & Kroemer, G.
- Affiliations
- Sorbonne Paris Cité (FR)
- Howard Hughes Medical Institute (US)
- St. Jude Children's Research Hospital (US)
- Karolinska University Hospital (SE)
- Corresponding author
- Galluzzi, Lorenzo
- Venue
- Nature Reviews Drug Discovery
- Published
- 2017-05-19
- Volume
- 16
- Issue
- 7
- Pages
- 487-511
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- PMC
- PMC5713640
- OpenAlex
- W2615994102
- Cited by
- 842
- References
- 307
- Citations by year
- 2026: 47 · 2025: 63 · 2024: 90 · 2023: 90 · 2022: 103 · 2021: 93 · 2020: 118 · 2019: 113 · 2018: 95 · 2017: 30
- FWCI
- 12.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (cc-by)
- Funders
- National Cancer Institute (R01CA109618)
- National Institute of Allergy and Infectious Diseases (U19AI109725)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- autophagy, autophagy modulators, drug development, cancer, neurodegenerative diseases, cardiovascular disease, infectious diseases, homeostasis, therapeutic target
- MeSH terms
- Animals, Autophagy, Heart Diseases, Humans, Neoplasms, Drug Design, Neurodegenerative Diseases, Molecular Targeted Therapy
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