PNPLA3 (Patatin Like Phospholipase Domain Containing 3)

By integrating germline (GWAS-based) and somatic evidence, this study provides a comprehensive view of HCC pathogenesis. This integrated strategy successfully identified a core set of genes and proteins with potential causal links to HCC, elucidating their functional convergence in cancer biology. These findings offer novel molecular insights and candidate targets for precise diagnosis, prognostic assessment, and targeted therapy of HCC, laying a solid foundation for future translational research.

Inherited and somatic variants can influence hepatocellular carcinoma risk through direct effects on chronic liver disease progression and/or through specific cancer-promoting pathways involving telomere maintenance and WNT signalling. Although polygenic risk scores represent a promising approach for risk stratification, current implementations face important limitations that must be addressed before achieving their full clinical potential.

Patients with the PNPLA3 CG/GG genotype, especially those with progressive fibrosis, have a high risk of recurrence after liver resection. PNPLA3 genotyping may help identify patients at high risk of late recurrence who require careful long-term surveillance.

The stepwise increase in HCC risk with higher numbers of risk alleles suggests their potential utility as biomarkers to identify high-risk individuals without a history of chronic hepatitis B or C virus infection. These findings provide a foundation for genetic risk stratification and precision prevention strategies in populations where non-viral etiologies of HCC are becoming increasingly important.

Non-cirrhotic MASLD-HCC is a distinct oncogenic entity driven by metabolic-immune interplay. Its recognition necessitates a shift in clinical paradigm: (1) surveillance strategies must incorporate metabolic and genetic risk factors beyond cirrhosis; (2) the unique TME may predict immunotherapy efficacy, urging etiology-specific trial design; and (3) a precision oncology framework integrating molecular subtyping and biomarker profiling is essential for early detection and tailored management of this growing patient population.

P1, N=176, Active, not recruiting, Eli Lilly and Company | Trial completion date: Oct 2026 --> May 2026 | Trial primary completion date: Oct 2026 --> May 2026 | Recruiting --> Active, not recruiting

The frequency of rs738409-G alleles was associated with a dose-dependent increase in HCC risk and was independent of other clinical risk factors. Among participants who were male, overweight, and those with diabetes, the risk of HCC was further elevated among those with rs738409-G alleles. These data may be helpful for the development of future risk stratification strategies.

These guidelines are intended for routine clinical use, with a specific focus on particular groups when needed. Abbreviations: ALD, Alcoholic liver disease; ALT, Alanine aminotransferase; AMAGE, African Middle East Association of Gastroenterology; AST, Aspartate transaminase; AUC, Area under the curve; BMI, Body mass index; CAP, Controlled attenuation parameter; CKD, Chronic kidney disease; CRN, Clinical Research Network; CSPH, Clinically significant portal hypertension; CT, Computed tomography; CVD, Cardiovascular diseases; DALY, Disability-adjusted life years; EGD, Esophagogastroduodenoscopy; EUS-PPG, Endoscopic ultrasound-derived portal pressure gradient; FIB-4, Fibrosis-4 Index; FLI, Fatty liver index; FLIP, Fatty Liver Inhibition of Progression; GCKR, Glucokinase regulator gene; GRADE, Grading of Recommendation, Assessment, Development, and Evaluation; HCC, Hepatocellular carcinoma; HDL, High-density lipoprotein; HOMA-IR, Homeostasis model assessment of insulin resistance; hsCRP, High-sensitivity C-reactive protein; HSD17B13, Hydroxysteroid 17-beta dehydrogenase 13; HSI, Hepatic steatosis index; HVPG, Hepatic venous pressure gradient; LSM, Liver stiffness measurement; MAFLD, Metabolic dysfunction-associated fatty liver disease; MASH, Metabolic dysfunction-associated steatohepatitis; MBOAT7, Membrane-bound O-acyltransferase domain-containing 7; MENA, Middle East and North Africa; MRE, Magnetic resonance elastography; MRI, Magnetic resonance imaging; MRI-PDFF, Magnetic resonance imaging-proton density fat fraction; MRS, Magnetic resonance spectroscopy; NAFLD, Non-alcoholic fatty liver disease; NAS, NAFLD activity score; NITs, Non-invasive tests; PH, Portal hypertension; PNPLA3, Patatin-like phospholipase domain-containing 3; SAF, Steatosis, activity, fibrosis (score); SSM, Spleen stiffness measurement; T2DM, Type 2 diabetes mellitus; TM6SF2, Transmembrane 6 superfamily member 2; VCTE, Vibration-controlled transient elastography.

The PNPLA3 p.I148M genotype was not associated with altered levels of microRNAs. Serum microRNAs, in particular miR-4651, may serve as additional biomarkers in patients with steatotic liver disease.

We demonstrate that TAG in peri-mitochondrial LDs functions as a ROS scavenger, enabling CSCs to survive in hyperoxidative environments. Targeting the signaling pathways involved in TAG synthesis presents a potential strategy for eradicating CSCs.

With a better understanding of the genetic factors involved in the pathogenesis of SLD, significant advancements have been made in diagnostics and therapeutics. This review explores the role of genetic factors in the disease's development, discusses current advancements in non-invasive diagnostic modalities, and examines therapeutic improvements based on these genetic insights to achieve better outcomes.

These findings underscore the importance of asparaginase phenotype-related SNP, ADSL (793-49A > C), in personalized treatment strategies based on genetic profiling and clinical parameters, potentially enhancing therapeutic efficacy and patient outcomes in pediatric BCP-ALL.