Both obesity and esophageal adenocarcinoma (EAC) rates have increased sharply in the United States and Western Europe in recent years. EAC is a classic example of obesity-related cancer where the risk of EAC increases with increasing body mass index. Pathologically altered visceral fat in obesity appears to play a key role in this process. Visceral obesity may promote EAC by directly affecting gastroesophageal reflux disease and Barrett’s esophagus (BE), as well as a less reflux-dependent effect, including the release of pro-inflammatory adipokines and insulin resistance. Deregulation of adipokine production, such as the shift to an increased amount of leptin relative to “protective” adiponectin, has been implicated in the pathogenesis of BE and EAC. This review discusses not only the epidemiology and pathophysiology of obesity in BE and EAC, but also molecular alterations at the level of mRNA and proteins associated with these esophageal pathologies and the potential role of adipokines and myokines in these disorders. Particular attention is given to discussing the possible crosstalk of adipokines and myokines during exercise. It is concluded that lifestyle interventions to increase regular physical activity could be helpful as a promising strategy for preventing the development of BE and EAC.

Recently discovered irisin, a member of the myokines family, is a potential mediator of exercise-induced energy metabolism and a factor promoting browning of the white adipose tissue. Recent evidence indicates that this myokine, released from contracting muscles, can mediate the beneficial effects of exercise on health. Irisin may be a potential therapeutic agent against obesity and has been shown to play an important role in the protection of various cells, tissues, and organs due to its anti-inflammatory, antioxidative, and anti-cancer properties. Our aim was to review the recent experimental and clinical studies on irisin and its expression, release into the bloodstream, tissue targets, and potential contribution to the protective effects of exercise in the gastrointestinal tract. Particular emphasis was placed on inflammatory bowel disease, intestinal ischemia/reperfusion injury, periodontitis, and other digestive tract disorders, including carcinogenesis. Overall, irisin holds significant potential as a novel target molecule, offering a safe and therapeutic approach to treating various gastrointestinal diseases.

Barrett’s esophagus (BE) is a premalignant adaptation to chronic gastroesophageal reflux disease (GERD) and the principal precursor lesion of esophageal adenocarcinoma (EAC). Carbon monoxide (CO), an endogenous gaseous mediator generated by heme oxygenases, regulates cellular homeostasis, stress responses, and survival pathways; however, its role in BE progression and EAC remains poorly understood. We investigated the biological and transcriptional effects of increased CO bioavailability in cellular models representing distinct stages of disease progression. Non-transformed esophageal squamous epithelial cells (NES-G2T), BE cells (BAR-T), and EAC-derived OE19 and OE33 cells were exposed to the CO donor CORM-A1 or its CO-depleted structural control (iCORM-A1). Cellular metabolic activity was assessed by the MTT assay, apoptosis by Annexin V/PI flow cytometry, and transcriptomic alterations by RNA sequencing in BAR-T, OE19, and OE33 cells following CORM-A1 treatment. Transient CO exposure was well tolerated by NES-G2T cells, with no significant effects on metabolic activity or apoptosis. While BAR-T cells showed alterations in MTT-derived metabolic activity, they exhibited only limited apoptotic changes following CORM-A1 exposure, indicating that the reduced metabolic activity was not accompanied by significant apoptotic cell death. In contrast, CORM-A1 induced a reduction in metabolic activity and increased apoptotic cell death in EAC-derived OE19 and OE33 cells. At 500 μM, CORM-A1 reduced metabolic activity of both EAC cell lines below 75% of the untreated control and exerted a significantly greater reduction in metabolic activity than iCORM-A1, suggesting a contribution of CO release to the observed response. Flow cytometric analyses confirmed a noticeable apoptotic response to CORM-A1 in both EAC cell lines. RNA sequencing revealed marked, highly cell type-dependent transcriptional responses to CO exposure. Non-neoplastic BAR-T cells exhibited the most pronounced transcriptomic remodeling, predominantly affecting pathways related to epithelial differentiation, tissue homeostasis, and extracellular matrix organization. In contrast, OE33 and OE19 cells displayed more restricted transcriptional responses that preferentially involved growth factor signaling, cellular adaptation, inflammatory regulation, and tumor-microenvironment interactions. Collectively, these findings suggest that responsiveness to CO is shaped by the degree of neoplastic transformation, with BE mounting a broad adaptive transcriptional response, showing limited drug-induced apoptosis. However, malignant cells exhibit greater vulnerability to CORM-A1-induced programmed cell death despite undergoing more limited transcriptomic remodeling. These data identify CORM-A1-responsive pathways and CO signaling as potential therapeutic targets in EAC.