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However, the underlying mechanism of HIF\u20101\u03b1 and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate the effects of hypoxia\u2010induced HIF\u20101\u03b1 on the development of gastric mucosal lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Portal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)\u2010induced mouse models in\n                      <jats:italic>METTL3<\/jats:italic>\n                      mutant or\n                      <jats:italic>NLRP3<\/jats:italic>\n                      \u2010deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HIF\u20101\u03b1, which can mediate mitochondrial dysfunction via upregulation of METTL3\/IGF2BP3\u2010dependent dynamin\u2010related protein 1 (Drp1) N6\u2010methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF\u20101\u03b1 with PX\u2010478, inhibiting Drp1\u2010dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi\u20101) treatment or\n                      <jats:italic>METTL3<\/jats:italic>\n                      mutation alleviated this process. Furthermore, HIF\u20101\u03b1 influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF\u20101\u03b1\u2010induced Drp1\u2010dependent mitochondrial fission also enhanced glycolysis. Drp1\u2010dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Under hypoxic conditions, HIF\u20101\u03b1 enhances mitochondrial dysfunction via Drp1\u2010dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.<\/jats:p>\n                  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