Perspective on alcohol-induced organ damage via autophagy-dependent cellular changes

Abstract

Alcohol-induced organ damage is a major global health concern and a leading cause of disability and mortality. In addition to the liver, chronic alcohol consumption adversely affects multiple organ systems, including the cardiovascular and neuromuscular systems, the gastrointestinal tract, adipose tissue, kidneys, pancreas, and the brain. Organ damage begins with necrosis (cell death) followed by tissue injury, which triggers immune responses aimed at tissue repair. However, with continued heavy drinking, these reparative responses transition into inflammatory responses which exacerbate tissue injury and accelerate disease progression. Macroautophagy, commonly referred to as autophagy, is a vital and evolutionarily-conserved digestive process in eukaryotic cells. While autophagy is well known for degrading obsolete proteins, and damaged organelles to prevent their accumulation, autophagy also plays critical roles in regulating innate and adaptive immunity and in modulating inflammation. This review describes evidence that chronic alcohol exposure and chronic alcohol consumption impair autophagy, contributing to dysfunction across multiple organ systems. We and others have explored the mechanisms by which alcohol disrupts autophagy to cause organ damage. This review aims to establish a cohesive understanding of these intracellular processes, which is essential for guiding future research toward targeting autophagy as a therapeutic strategy for alcohol-induced tissue injury. In summary, this comprehensive review integrates evidence from preclinical studies to present a unified perspective on how alcohol induces autophagy dysregulation and contributes to organ damage. It also highlights evidence-based recommendations from leading researchers in the field, offering valuable insights to advance autophagy-targeted therapies for mitigating the effects of alcohol-induced organ injury.

Fig. 1

Autophagy Pathway. Details provided in the text. This figure, along with all others in the review, was created using BioRender Scientific Image and Illustration Software (BioRender.com).

Fig. 2

Schematic illustration of the impact of acute and chronic alcohol on autophagy in the liver. In hepatocytes, alcohol (ethanol/EtOH) is metabolized by ADH and CYP2E1 into AcAld. CYP2E1 is a major source of ROS during alcohol metabolism, producing superoxide (O₂•^-) and hydrogen peroxide (H₂O₂), with hydroxyl radical (•OH) generated downstream via the Fenton/Haber–Weiss reaction. These ROS, together with reactive nitrogen species (e.g., peroxynitrite) formed from the reaction of O₂•^- with nitric oxide, contribute to oxidative modification of proteins, lipids, and organelle membranes. Acute EtOH metabolism causes mitochondrial depolarization (mtDepo) and lipid accumulation. It also promotes TFEB nuclear translocation, which activates transcription of autophagy-related genes (ATGs) and lysosome biogenesis. These processes enhance mitophagy and help minimize EtOH-induced liver injury. In contrast, chronic EtOH exposure disrupts lysosomal function and dysregulates TFEB, thereby promoting hepatocellular damage. Persistent AcAld production, together with lipid peroxidation–derived reactive aldehydes (e.g., 4-HNE, MDA), induces tubulin acetylation and protein adduction, impairing microtubule polymerization and disrupting autophagosome (AV)–lysosome (LYS) fusion. This fusion defect impairs degradation of lipids and proteins, contributing to steatosis and proteopathy, which are hallmark features of alcohol-induced liver disease. Chronic EtOH exposure likely increases lysosomal pH by interfering with the proton pump that maintains the acidic environment of the lysosomal lumen, thereby reducing degradative capacity. It also promotes lysosomal membrane fragility. Reactive aldehydes from alcohol metabolism are also likely to damage lysosomal membranes (indicated in the figure with a question mark to reflect this proposed mechanism). Comorbid conditions such as HIV and HCV infection further exacerbate lysosomal dysfunction by damaging the lysosomal membrane, leading to leakage of lysosomal contents. This leakage, particularly of Cathepsins, causes mitochondrial injury, promotes reactive oxygen species (ROS) generation, and triggers mitochondrial DNA (mtDNA) release. These events initiate apoptosis and lead to the release of apoptotic bodies, mtDNA, and extracellular vehicles (EVs). These components are taken up by hepatic stellate cells (HSCs) and macrophages, amplifying liver injury. EtOH enhances autophagy in HSCs, providing energy and cytoprotection that support their transition to a fibrogenic phenotype. Conversely, chronic EtOH suppresses autophagy in macrophages, promoting a proinflammatory M1 phenotype and contributing to liver inflammation. Dotted arrows: acute EtOH effects; Brown arrows/block symbol: chronic EtOH effects; Black arrows: downstream effects; Short thick black arrows: increase or decrease in effect.

Fig. 3

Schematic illustration of impact of alcohol on autophagy in GI tract. Alcohol metabolism in the gastric and intestinal epithelium via CYP2E1 generates superoxide (O₂•^-) and hydrogen peroxide (H₂O₂), with hydroxyl radicals (•OH) formed downstream through Fenton chemistry. CYP2E1-derived reactive oxidants likely disrupt autophagy in the gastric mucosa by inhibiting AMPK and activating mTOR signaling. mTOR activation downregulates key autophagy proteins such as Beclin-1 and LC3B, impairing autophagosome formation and autophagic flux. This leads to defective clearance of damaged organelles, including mitochondria (mitophagy). Damaged mitochondria release reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), which activate the NLRP3 inflammasome and promote apoptosis, ultimately contributing to gastric mucosal injury. Additionally, acetaldehyde and oxidative stress further exacerbate epithelial barrier damage by promoting ER stress, tight junction degradation, and inflammatory signaling. These immune and oxidative responses amplify mucosal damage. Pharmacological treatment with rebamipide restores autophagy by activating MAPK/ERK pathways independently of Beclin-1 and mTOR. This enhances autophagy-related gene expression (e.g., LC3-II, ATG 5/7), reduces SQSTM1/p62 accumulation, and protects against EtOH-induced apoptosis and inflammation in gastric epithelial cells. Arrows and symbols have the same meaning as described in Fig. 1.

Fig. 4

Schematic illustration of impact of alcohol on autophagy in the Pancreas. In pancreatic acinar cells, alcohol (ethanol) reduces the expression of VAMP1, a protein essential for autophagosome (AV) formation, and increases ATG4B, a negative regulator of autophagosome biogenesis. These changes disrupt AV formation. EtOH also decreases the lysosomal membrane protein LAMP2, compromising lysosomal (LYS) function, and inhibits autophagosome–lysosome fusion. In addition, EtOH blocks TFEB nuclear localization, further suppressing the autophagy pathway. Collectively, these disruptions downregulate autophagy in pancreatic acinar cells, leading to the accumulation of damaged organelles. This contributes to the premature activation of trypsin within the acinar cells, resulting in cell necrosis and the development of alcohol-induced pancreatitis. Arrows and symbols have the same meaning as described in Fig. 1.

Fig. 5

Schematic representation of autophagy-lysosome dysregulation and downstream pathological outcomes across organs following alcohol exposure. In summary, chronic alcohol consumption disrupts autophagy, shifting it from a protective mechanism to a driver of organ dysfunction and systemic inflammation. Although therapeutic targeting of autophagy holds promise, it is important to note that the majority of data summarized in this review are derived from rodent models. Translation of these findings to human biology remains essential. Preliminary data from ongoing studies in human liver tissue, including work from the Thomes laboratory, suggest that key autophagy-related mechanisms observed in rodents may not be fully conserved in humans. This highlights the need for caution when extrapolating preclinical findings and underscores the importance of validating mechanistic models in human tissues and clinical cohorts. Advancing this line of investigation will be critical for developing targeted interventions that effectively mitigate alcohol-related organ damage in human populations.