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In the lung, autophagy contributes to normal development, epithelial integrity, mitochondrial quality control, and immune regulation. Emerging evidence indicates that environmental exposures such as cigarette smoke (CS), electronic cigarette (EC) aerosols, and nicotine profoundly disrupt these processes, contributing to both chronic lung disease and developmental programming of respiratory pathology. In this review, we propose a unifying framework in which autophagy functions as a redox\u2010modulated rheostat that integrates oxidative, metabolic, and epigenetic stress signals triggered by smoke and nicotine exposure. Under physiological conditions, autophagy mitigates oxidative stress by removing dysfunctional mitochondria and maintaining proteostasis. However, chronic exposure to CS or EC aerosols generates excessive reactive oxygen species, impairs lysosomal degradation, and disrupts mitochondrial quality control, shifting autophagy from an adaptive protective response to a maladaptive driver of epithelial injury, inflammation, and tissue remodeling. Integrating experimental and clinical evidence, we identify four mechanistic axes underlying smoke\u2010induced autophagy dysregulation: lysosomal dysfunction with TFEB suppression, mitochondrial redox amplification, disruption of selective autophagy pathways (including mitophagy, ER\u2010phagy, xenophagy, and lipophagy), and immune polarization associated with inflammasome activation and cellular senescence. Importantly, maternal smoke and EC exposure similarly perturb autophagy in the placenta and fetal lung, altering developmental trajectories and increasing susceptibility to asthma and chronic lung disease. Viewing autophagy as a dynamic, redox\u2010sensitive rheostat highlights new therapeutic opportunities to restore autophagic flux, lysosomal competence, and mitochondrial quality control in smoke\u2010 and nicotine\u2010related lung disease.<\/jats:p>","DOI":"10.1002\/cph4.70167","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T05:22:24Z","timestamp":1778304144000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Autophagy as a Redox Rheostat Linking Cigarette Smoke, Electronic Cigarettes, and Nicotine Exposure to Lung Development, Disease, and Interorgan Communication"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7036-1176","authenticated-orcid":false,"given":"Noushin","family":"Lotfi","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center  Torrance California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahid","family":"Rezaei","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine Lorestan University of Medical Sciences  Khorramabad Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gourav","family":"Chandan","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center  Torrance California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omid","family":"Akbari","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virender K.","family":"Rehan","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center  Torrance California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_2_22_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402277"},{"key":"e_1_2_22_3_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-268276"},{"key":"e_1_2_22_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.70065"},{"key":"e_1_2_22_5_1","article-title":"Impact of e\u2010Cigarette Exposure on Circadian Regulatory Proteins and Inflammatory Responses","volume":"17","author":"Alzubi A.","year":"2026","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_22_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/eep\/dvw020"},{"key":"e_1_2_22_7_1","unstructured":"Baimei H.n.d.Reciprocal Interaction Between Autophagy and ER Stress in Cigarette Smoke Extract\u2013Induced Apoptosis."},{"key":"e_1_2_22_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00427.2009"},{"key":"e_1_2_22_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41479-020-00075-2"},{"key":"e_1_2_22_10_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2016.6842"},{"key":"e_1_2_22_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.06.017"},{"key":"e_1_2_22_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2014.81"},{"issue":"6","key":"e_1_2_22_13_1","first-page":"1234","article-title":"Cigarette Smoke\u2010Induced Oxidative Stress and Autophagy Dysregulation in Lung Disease","volume":"12","author":"Cha S.","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"e_1_2_22_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3521"},{"key":"e_1_2_22_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11596-025-00074-8"},{"key":"e_1_2_22_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116666"},{"key":"e_1_2_22_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3532"},{"key":"e_1_2_22_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.150"},{"key":"e_1_2_22_19_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.112.106617"},{"issue":"1","key":"e_1_2_22_20_1","first-page":"L135","article-title":"Chronic Electronic Cigarette Vapor Inhalation Induces Features of COPD in Mice","volume":"311","author":"Garcia\u2010Arcos I. 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