{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T16:43:04Z","timestamp":1793032984744,"version":"4.5.0"},"reference-count":147,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, also known clinically as gastric MALT lymphoma (GML) or MALToma, is an indolent B-cell neoplasm strongly associated with chronic Helicobacter pylori (H. pylori) infection. While early-stage disease is based on persistent antigenic stimulation and chronic inflammation, the metabolic and molecular transitions that drive monoclonal B-cell autonomy remain poorly understood. Importantly, H. pylori maintain this long-term colonization by defusing the host\u2019s innate immunity; specifically, its lipid A portion features unique elongated acyl chains, composed of 16\u201318 carbon atoms, that fail to bind to and activate host TLR4\/MD2 receptors, resulting in exceptionally weak endotoxic potency. Persistent colonization relies on key oncoproteins, particularly cytotoxin-associated gene A (CagA) and vacuolar cytotoxin A (VacA), which orchestrate early inflammatory infiltration (neutrophils, Th1, Th2 and Th17 cells) before shifting the microenvironment toward a suppressive regulatory T cell (Treg) phenotype. In this study, we propose a new critical step in the oncogenesis of gastric metastasis: chronic mitochondrial and immunometabolic adaptation within the gastric microenvironment. We claim that H. pylori act not only as a trigger for infection but also as a chronic driver of mitochondrial adaptation to oxidative stress and hypoxia, which subsequently results in defective mitophagy. CagA- and VacA-mediated mitochondrial damage induces reactive oxygen species (ROS) and functional hypoxia, stabilizing HIF-1\u03b1 to force a glycolytic metabolic shift, while incomplete mitophagy rescues metabolically altered, apoptosis-resistant clones to drive monoclonal B-cell expansion. Within this ecological-microenvironmental framework, the predominantly cytoplasmic sequestration of BCL10 and the NF-\u03baB subunit p65 observed in GML is reinterpreted not as evidence of signaling inactivity, but as a dynamically regulated adaptive state. This configuration is orchestrated by mitochondrial stress responses that enable adaptation to the chronic microenvironmental pressures imposed by H. pylori, acting in concert with the metabolic programs governed by MYC, NRF2, and BCL2. Overall, this review outlines the multi-step pathogenesis of H. pylori-mediated GML, highlighting how mitochondrial dysfunction and metabolic remodeling drive the transition from chronic infection to malignant transformation.<\/jats:p>","DOI":"10.3390\/diseases14080280","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:14:46Z","timestamp":1785917686000},"page":"280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Beyond Infection: Mitochondrial Reprogramming and Immunometabolic Adaptation in Helicobacter pylori-Associated Gastric MALT Lymphoma"],"prefix":"10.3390","volume":"14","author":[{"given":"Ciro","family":"Gargiulo Isacco","sequence":"first","affiliation":[{"name":"Department of Interdisciplinary Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1672-3292","authenticated-orcid":false,"given":"Van Hung","family":"Pham","sequence":"additional","affiliation":[{"name":"Viet Nam Research and Development Institute of Clinical Microbiology, Ho Chi Minh City 756000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huong Thien","family":"Pham","sequence":"additional","affiliation":[{"name":"Viet Nam Research and Development Institute of Clinical Microbiology, Ho Chi Minh City 756000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieu Cao Diem","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5722-8581","authenticated-orcid":false,"given":"Toai Cong","family":"Tran","sequence":"additional","affiliation":[{"name":"Basic Medical Sciences Faculty, Pham Ngoc Thach University of Medicine, Ho Chi Minh City 740500, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thach Huy","family":"Le","sequence":"additional","affiliation":[{"name":"Ninh Thuan General Hospital, Khanh Hoa City 59123, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicita","family":"Jirillo","sequence":"additional","affiliation":[{"name":"Independent Researcher, R&D, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Jirillo","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5671-8124","authenticated-orcid":false,"given":"Luigi","family":"Santacroce","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1080\/10428194.2023.2297939","article-title":"The 5th edition of the World Health Organization Classification of mature lymphoid and stromal tumors\u2014An overview and update","volume":"65","author":"Attygalle","year":"2024","journal-title":"Leuk. 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