Abstract 3388: Targeting liver specific βII-Spectrin to prevent the development of metabolic dysfunction associated steatohepatitis (MASH) through CEACAM1 axis

Abstract Background: Obesity and pro-inflammatory alteration of the gut microbiome are risk factors for gastrointestinal (GI) cancers, including liver cancer (HCC). Dysregulated TGF-β signaling and loss of CEACAM1 activity are implicated in fatty liver disease. Clinically, 40% of human liver and GI cancers have genetic alterations in the TGF-β pathway members. CEACAM1 expression is significantly decreased in the liver of patients with Metabolic dysfunction-associated steatohepatitis (MASH). In contrast, in hepatocellular carcinoma (HCC), high CEACAM1 is associated with invasion, metastasis and poor prognosis. We hypothesized that TGF-β signaling and βII-Spectrin modulate MASH and HCC through CEACAM1. Methods: Wild type and the liver-specific βII-Spectrin (Sptbn1) knockout (LSKO) mice fed a high-fat diet (HFD) or Western diet (WD) and analyzed for Ceacam1 expression, changes in immune cell population, liver inflammation, and cancer. We used Alphafold and molecular modeling to identify the CEACAM1 and SPTBN1 interaction sites. Results: Single cell sequencing analysis of MASH mice liver revealed that Ceacam1 expression is significantly decreased in hepatocytes. Interestingly, we found that CEACAM1 levels are restored to normal in tissues from liver-specific βII-Spectrin knockout (LSKO) mice. Transcriptomic and multiplex imaging analysis suggest that proinflammatory TGF-β signaling is activated and infiltration of CD11b+ cells is increased in MASH liver. These phenotypes are blocked in LSKO mice. Furthermore, siRNA-knockdown of βII-Spectrin blocks diet-induced obesity, fibrosis, lipid accumulation, tissue damage, and cancer susceptibility. We have also found that CEACAM1 interacts with the Smad3 adaptor, βII-Spectrin. Furthermore, structural analysis of CECAM1 and βII-Spectrin revealed critical residues involved in the interaction. Conclusion: These data suggest that βII-Spectrin regulates CEACAM1 expression in the liver and is a potential target for therapeutic intervention to treat MASH and prevent progression to HCC. Citation Format: Krishanu Bhowmick, Kazufumi Ohshiro, Xiyan Xiang, Sahara John, Xiaochun Yang, Nicole Beauchemin, Mohammad I. Hassan, Taj Mohammad, Lopa Mishra. Targeting liver specific βII-Spectrin to prevent the development of metabolic dysfunction associated steatohepatitis (MASH) through CEACAM1 axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3388.