Background and Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of HCC. Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD. Approach and Results: We considered individuals with MASLD-HCC (n=208) and controls with (n =414) and without (n =259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with variant allele frequency ≥2%. CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53, and ASXL1, and correlated with age (p<0.0001) and advanced liver fibrosis (p=0.001). Higher aspartate aminotransferase levels predicted non-DNMT3A-CHIP, in particular with variant allele frequency ≥10% (OR: 1.14, 1.03 −1.28 and OR: 1.30, 1.12 −1.49, respectively, p<0.05). After adjustment for sex, diabetes, and a polygenic risk, a score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30 −3.15, p=0.02), and with HCC even after further adjustment for cirrhosis (OR: 1.81, 1.11 −2.00, 1.30 −3.15, p=0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non-DNTM3A-CHIP, and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR: 2.45, 1.35 −4.53; OR: 4.8, 1.60 -17.0, p=0.02). Conclusions: We observed an independent association between CHIP, particularly related to non-DNTM3A and TET2 genetic lesions and MASLD-HCC.

OTX homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. Reactivation of OTX genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the “toolbox” to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets.

Introduction . Müller glial cells typically activate to react to hypoxic tissue damage in several retinal diseases. We evaluated the in vitro response to a hypoxia‐mimicking stimulus on the expression of a set of genes, known to contribute to eye morphogenesis and cell differentiation. Materials and Methods . A MIO‐M1 Müller cell line was cultured in a hypoxia‐mimicking environment by the addition of cobalt chloride to the culture medium, followed by a recovery time in which we mimic restoration from the hypoxic insult. The HIF‐1 α protein and VEGF‐A gene expression were quantified to verify the induction of a hypoxia‐like state. Results . Among the genes under study, we did not observe any difference in the expression levels of Otx1 and Otx2 during treatment; conversely, Otx1 was overexpressed during recovery steps. The VEGF‐A gene was strongly upregulated at both the CoCl ₂ and recovery time points. The transactivated isoform (TA) of the TP73 gene showed an overexpression in long‐term exposure to the hypoxic stimulus with a further increase after recovery. Discussion . Our molecular analysis is able to describe the activation of a set of genes, never before described, that can drive the response to a hypoxia‐like status. The improved comprehension of these cellular events will be useful for designing new therapeutical approaches for retinal pathologies.

The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) protein is an acyltransferase catalyzing arachidonic acid incorporation into lysophosphatidylinositol. Patients with rare, biallelic loss-of-function variants of the MBOAT7 gene display intellectual disability with neurodevelopmental defects. The rs641738 inherited variant associated with reduced hepatic MBOAT7 expression has been linked to steatotic liver disease susceptibility. However, the impact of biallelic loss-of-function MBOAT7 variants on liver disease is not known. We report on a 2-year-old girl with MBOAT7-related intellectual disability and steatotic liver disease, confirming that MBOAT7 loss-of-function predisposes to liver disease.

Background and Aims: In patients with steatotic liver diseases (SLD), genetic factors may account for severe liver involvement despite mild or absence of triggering factors or a strong family history. Aim of this study was to examine the diagnostic uptake of targeted sequencing (TS), covering both coding and non‐coding regions, of a broad panel of 82 liver and lipid metabolism genes in patients with unexplained SLD. Methods: We enrolled 49 adult patients with SLD and a suspected genetic contribution. Genetic variants were detected through a customised TS panel, whereas the contribution of common genetic variation to the individual susceptibility to SLD was captured by a polygenic risk score (SLD‐PRS). Results: A diagnosis of rare Mendelian disorder was established in 11 patients (22%), independently of age or family history. Rare variants possibly contributing to clinical phenotype were detected in additional 29 patients (59%). Increased SLD‐PRS values were detected in 17 patients (35%), enabling an increase in diagnostic uptake of 24%, especially in those without a strong family history ( p = 0.03). Genetic diagnosis allowed refinement of clinical management in 23 (47%) patients. Conclusions: The diagnostic uptake of TS was 22% for Mendelian disorder and 59% for possible contribution to clinical phenotype in selected adult patients with SLD. Evaluation of common variants, as captured by SLD‐PRS, yields complementary information increasing the overall utility of the genetic examination.