Search Results (6,419)

Background: As a key regulator of centrosome duplication, polo-like kinase 4 (PLK4) is abnormally overexpressed in various tumors and has emerged as an important target for the development of antitumor drugs. Methods: In this study, based on the lead compound ZSL-M001 (PLK4 IC50 = 3.0 μM) previously obtained by our research group, we designed and synthesized 28 novel quinazoline-based PLK4 inhibitors to enhance kinase inhibitory activity using side-chain extension strategies. Results: Among them, compound H24 (PLK4 IC50 < 0.1 nM) exhibited favorable in vitro antiproliferative activity against TRIM37-amplified MCF-7 breast cancer cells (MCF-7 IC50 = 2.37 ± 0.26 μM) and TRIM37-amplified neuroblastoma IMR-32 cells (IMR-32 IC50 = 1.28 ± 0.04 μM). Its activity was superior to that of the positive control LCR-263. Further in vitro biological evaluation demonstrated that H24 inhibited the colony formation of MCF-7 cells in a concentration-dependent manner, induced S/G2-phase cell-cycle arrest, and promoted apoptosis. H24 also showed favorable metabolic stability in human liver microsomes, with a half-life of 61.3 min. However, no obvious TRIM37 amplification-dependent cellular selectivity was observed in TRIM37 non-highly amplified A549 cells or normal human embryonic kidney HEK-293T cells. Given the suboptimal selectivity of the in vitro antiproliferative activity, Aurora kinase A, which shares high homology with PLK4, was selected for further evaluation of its selectivity. The IC50 for Aurora A inhibition was determined to be 151.2 nM, indicating that its broader kinase selectivity remains to be established. Conclusions: In summary, H24 is a highly potent biochemical PLK4 inhibitor and provides a useful lead scaffold for further optimization rather than a fully selective cellular candidate at the current stage. Full article

Purpose: Systemic immunotherapy is less effective in patients with liver metastases. Immunoembolization could potentially overcome the immunosuppressive tumor microenvironment, but the optimal immunotherapy agent, embolic, and release kinetics are unknown. Methods: A wide range of immunotherapy agents (cytokines, small molecules, and oligonucleotides) were loaded onto various embolics (stabilized lipiodol emulsions, microspheres-in-lipiodol, LC beads, and PLGA microspheres). Drug loading and release kinetics were evaluated in vitro. A pilot study of transarterial immunoembolization was performed in a pig liver tumor model, using extended release lipiodol/CpG-STAT3ASO formulations. CpG-STAT3ASO is a first-in-class dual-function immunotherapy agent that both stimulates the anti-tumor immune response, and counters immunosuppression in immunologically cold tumors. Safety, pharmacokinetics and efficacy were evaluated in pigs. Results: Immunotherapy-loaded embolics released drug with a half-life ranging from days to weeks in vitro, and up to four days in pig liver tumors (depending on the formulation). A stabilized lipiodol emulsion demonstrated 100% burst release (within five minutes after immunoembolization), compared to <1% burst release with microspheres-in-lipiodol. Immunoembolization using lipiodol/CpG-STAT3ASO resulted in decreased size of pig liver tumors, compared to bland embolization. No adverse events were seen, based on clinical, laboratory, and radiographic evaluation, but peritoneal adhesions were observed in association with immunoembolization using microspheres-in-lipiodol. Conclusions: Extended-release immunotherapy-loaded embolics generate sustained intratumoral delivery of immune stimulants. A pilot study of immunoembolization of pig liver tumors showed decreased tumor size, compared to bland embolization, with no autoimmune adverse events. Full article

Background/Objectives: Primary liver and intrahepatic bile duct cancers remain important causes of cancer morbidity and mortality worldwide, yet contemporary nationwide data on affected populations in Poland are limited. This study evaluated sociodemographic patterns of first-time hospitalizations due to malignant neoplasms of the liver and intrahepatic bile ducts in Poland during 2012–2023. Methods: Data were obtained from the Nationwide General Hospital Morbidity Study and included 30,898 first-time hospitalizations identified using the ICD-10 category C22. First-time hospitalization rates were assessed according to sex, age, place of residence, disease subtype, length of stay, and comorbidities. Results: Men accounted for 57.7% of urban and 58.4% of rural cases and had significantly higher first-time hospitalization rates than women. These rates were higher among urban than rural residents (men: 9.5 vs. 6.0 per 100,000; women: 6.3 vs. 4.2 per 100,000). Liver cell carcinoma was the most frequent subtype (36.3%), followed by intrahepatic bile duct carcinoma (12.6%). Hospitalizations were uncommon before the age of 40 years and peaked in the 65–69-year age group. Mean age increased over time among men and urban women. In 2020, the number of first-time hospitalizations decreased from 2754 to 2060, corresponding to 694 fewer hospitalizations and a 25.2% decline compared with 2019. This decrease occurred against the background of nationwide reductions of 22.1% in patients treated in general-hospital wards and 8.1% in oncology-ward patients, suggesting that pandemic-related healthcare disruption may have contributed to the observed decline. Hospitalization rates subsequently increased. Rates for liver cell carcinoma remained relatively stable in most population groups, whereas those for intrahepatic bile duct carcinoma were significantly higher in 2020–2023 than in 2012–2019 across all sex and place-of-residence groups. Length-of-stay patterns were broadly similar across the analyzed groups, and diseases of the digestive system were the most common comorbidity category (23.1%). Conclusions: The findings demonstrate important sociodemographic differences and temporal changes in first-time hospitalizations due to malignant neoplasms of the liver and intrahepatic bile ducts in Poland. These findings suggest evolving epidemiological patterns and underscore the need for continued prevention, surveillance, and early detection efforts. Full article

Background: Metabolic and alcohol-associated liver disease (MetALD) has been associated with an increased risk of cancer. However, it remains unclear whether combinations of favorable, intermediate, and adverse lifestyle behaviors differentiate cancer risk within MetALD. Methods: We analyzed 25,712 participants with MetALD using UK Biobank. Smoking, moderate-to-vigorous physical activity (MVPA), and diet were classified into favorable, intermediate, and adverse categories. Favorable and adverse behavior counts ranged from 0 to 3, and a unified lifestyle profile was constructed. Cox proportional hazards models were used to analyze adjusted hazard ratios (aHRs) and 95% confidence interval (CI) for incidence of all cancers. Results: During 296,965 person-years of follow-up, 4416 incident cancers occurred. Compared with no favorable behaviors, those having two favorable behaviors showed significance 0.92 (95% CI, 0.84–1.00). Compared with no adverse behaviors, the aHRs were 1.06 (95% CI, 1.00–1.13), 1.15 (95% CI, 1.04–1.27), and 1.11 (95% CI, 0.84–1.47) for one, two, and three adverse behaviors, respectively (p for trend = 0.003). The mixed/intermediate profile was associated with higher cancer risk than the favorable profile (aHR, 1.09; 95% CI, 1.02–1.16), whereas the adverse-profile estimate was not statistically significant. Among individual lifestyle behaviors, current smoking was associated with a higher cancer risk than never smoking (aHR, 1.20; 95% CI, 1.09–1.32; p < 0.001). Conclusions: Among participants with MetALD, favorable and adverse behavior counts showed opposite adjusted trends in cancer risk. Current smoking showed the strongest association with cancer risk among the individual behaviors. Full article

Background: Based on the demonstrated survival benefits of gemcitabine plus cisplatin (GemCis) therapy in the TOPAZ-1 and KEYNOTE-966 trials, GemCis plus immune checkpoint inhibitor (ICI) therapy has become a standard first-line treatment for unresectable biliary tract cancer. However, its safety and efficacy in elderly patients and those requiring biliary drainage remain insufficiently evaluated in real-world practice. We aimed to evaluate the efficacy and safety of GemCis plus ICI therapy, with a focus on elderly patients and those requiring biliary drainage. Methods: We retrospectively analyzed the clinical characteristics of patients with unresectable biliary tract cancer treated with GemCis plus ICI at our institution between April 2022 and September 2025. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method, and prognostic factors were examined using Cox proportional hazards models. PFS and immune-related adverse events (irAEs) were compared between durvalumab and pembrolizumab. Results: Of the 51 patients diagnosed with unresectable biliary tract cancer during the observation period, 26 (51.0%) received GemCis plus ICI therapy. The median age was 73 years (range, 46–83 years), and 15 (57.7%) patients were male. Distant metastases were present in 22 patients (84.6%), and biliary drainage was performed in 15 (57.7%). The primary tumor sites were intrahepatic cholangiocarcinoma (n = 8), perihilar cholangiocarcinoma (n = 6), gallbladder cancer (n = 11), and cancer of unknown primary origin (n = 1). The ICIs used were durvalumab in 18 patients and pembrolizumab in eight patients. The median follow-up period was 214 days (range, 30–1114). The response rate was 28.6%, the disease control rate was 90.5%, and the transition rate to ICI maintenance therapy was 29.2%. IrAEs occurred in six patients (23.1%), with a significantly higher frequency in the pembrolizumab group than in the durvalumab group (50.0% vs. 11.1%). The median PFS was 8.2 months in the durvalumab group and 8.9 months in the pembrolizumab group, with no significant difference (p = 0.88). Multivariate analysis incorporating age, performance status, metastatic burden, and liver function confirmed that age ≥ 75 years remained the only independent predictor of shorter PFS (HR 5.62; 95% CI, 1.35–23.4; p = 0.02), whereas ICI regimen and biliary drainage were not significant prognostic factors. Conclusions: In clinical practice, GemCis plus ICI therapy showed no statistically significant difference in efficacy between ICI regimens in this small cohort, although this comparison was not statistically powered. Given the exploratory nature of these findings, the lower incidence of immune-related adverse events (irAEs) observed in the durvalumab group should be interpreted with caution. Age ≥ 75 years was associated with shorter PFS. Careful patient selection is warranted when considering GemCis plus ICI therapy in elderly patients with biliary tract cancer. Full article

Elastography is an ultrasound-based technique that enables the non-invasive assessment of tissue stiffness. In endoscopic ultrasound (EUS), elastography was initially introduced as a strain-based method, providing qualitative or semi-quantitative information on tissue deformation. More recent technological developments have enabled the integration of shear-wave-based elastography into EUS platforms, including shear-wave measurement (SWM), point shear-wave elastography (pSWE), and two-dimensional shear-wave elastography (2D-SWE). Unlike strain elastography, shear-wave techniques provide quantitative estimates of tissue stiffness by measuring shear-wave velocity or a derived elastic modulus. This invited narrative review summarizes the technical principles, terminology, quality-control requirements, and current clinical evidence for EUS-guided shear-wave-based elastography in pancreatic and hepatobiliary diseases. Because much of the available EUS literature derives from EUS-SWM or point SWE rather than true 2D-SWE, acquisition mode is a central determinant when interpreting clinical evidence and clinical readiness. Current data suggest that EUS-guided shear-wave-based elastography is technically feasible and biologically plausible, but its clinical maturity remains indication-specific. Evidence is most encouraging in chronic pancreatitis, early chronic pancreatitis, autoimmune pancreatitis activity monitoring, and selected endo-hepatology settings, particularly liver fibrosis assessment in patients in whom transabdominal techniques may be suboptimal. In contrast, available evidence does not support EUS-guided shear-wave-based elastography as a standalone diagnostic test for differentiating solid pancreatic lesions, including pancreatic ductal adenocarcinoma, because absolute stiffness values often overlap among malignant lesions, inflammatory masses, and background parenchyma. Before routine clinical implementation, standardized acquisition protocols, disease-specific cut-offs, multicenter reproducibility data, and evidence of incremental clinical value beyond established diagnostic pathways are required. Full article

Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression. Full article

Background: Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain leading causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide, and continue to represent a major challenge despite the growing contribution of alcohol-related and metabolic dysfunction-associated steatotic liver disease. Direct-acting antivirals now cure most patients with chronic HCV infection, while nucleos(t)ide analogues durably suppress HBV replication, producing a rapidly expanding population of treated and cured patients. Many nonetheless retain residual fibrosis, portal hypertension and long-term cancer risk, creating a need for non-invasive long-term liver assessment. Multiparametric ultrasound (MPUS) integrates the evaluation of morphology, fibrosis, steatosis, haemodynamics and perfusion within a single examination. Methods: Publications indexed in PubMed/MEDLINE, Scopus and Google Scholar between January 2000 and April 2026 were reviewed narratively, with priority given to international guidelines and consensus documents, meta-analyses, and prospective studies using histological, haemodynamic or clinical reference standards. Results: This narrative review summarises the evidence supporting MPUS in chronic viral hepatitis, covering elastographic fibrosis assessment, Baveno VII liver and spleen stiffness criteria for clinically significant portal hypertension, contrast-enhanced ultrasound characterisation of focal liver lesions, and emerging techniques such as microvascular and viscosity-sensitive imaging. Particular attention is given to the confounding effect of inflammatory activity on liver stiffness. MPUS is presented here as a proposed evaluation framework for organising complementary measurements within a single examination, and not as an approach of demonstrated clinical superiority: no comparative or outcome-based study has yet shown that acquiring these parameters together improves clinical decisions relative to the individual techniques applied according to current guidelines. Conclusions: Within this framework, the most plausible role of MPUS in the elimination era is longitudinal assessment of the treated liver, a proposition that requires prospective validation against clinical endpoints. Full article

Oleanolic acid is a naturally occurring pentacyclic triterpenoid with broad preclinical promise in inflammation, oxidative stress, liver injury, metabolic disorders, cancer-related models, skin disease, and wound repair. Its further development, however, is constrained by poor aqueous solubility, low and variable bioavailability, limited barrier transport, crystallinity, and strong dependence of biological response on the formulation used. These properties make oleanolic acid a useful example of a hydrophobic natural compound whose pharmacological performance is inseparable from delivery design. This review examines polymeric nanocarriers and polymer-assisted delivery platforms developed for oleanolic acid delivery. Polymeric nanocarriers discussed in the review include biodegradable PLA/PLGA nanoparticles, PEGylated polymeric nanoparticles, polymeric micelles, nanogels, hyaluronic-acid-based nanoprodrugs, and selected polymer-assisted hybrid nanostructures. Hydrogels, polymeric fiber membranes, local depots, and microneedle systems are included as route-enabling delivery platforms when the polymeric matrix directly contributes to OA incorporation, carrier stabilization, local retention, barrier bypass, or release control. Non-polymeric delivery systems are discussed only as comparators or when their performance depends on integration with a polymeric component. Rather than treating these carriers only as solubility enhancers, the review evaluates how polymer composition, carrier architecture, drug physical state, release behavior, and route of administration affect oleanolic acid exposure. Particular attention is given to controlled release, local retention, disease-oriented delivery, and critical quality attributes such as particle size, loading, encapsulation efficiency, solid-state form, stability, residual solvent, sterility, and batch-to-batch reproducibility. Representative quantitative data on carrier size, drug loading, encapsulation efficiency, release, stability, tissue exposure, and biological outcomes are compared to illustrate both formulation-specific performance and the substantial methodological heterogeneity of the available studies. The available evidence indicates that increased apparent solubility, increased biological exposure, and improved therapeutic response should be treated as related but distinct outcomes. The most realistic near-term opportunities may lie in local and tissue-targeted applications, including inflammatory skin disease, wound healing, dermal delivery, and osteoarthritis, where sustained target-site exposure may be more relevant than systemic bioavailability. Future progress will depend on demonstrating that each formulation provides reproducible, safe, and route-appropriate OA exposure, together with a measurable advantage over simpler delivery approaches. Full article

Exosomes are small extracellular vesicles that mediate intercellular communication and, in cancer, carry cargo that both reflects the donor tumor cell and influences recipient cells within local and distant microenvironments. Exosomal proteins and microRNAs have been reported individually across many cancer types, but rarely compared on a common basis; in this review, previously reported molecules from eight cancer categories—blood, breast, colon, kidney, liver, lung, prostate, and stomach—were compiled from curated repositories and re-analyzed within a single functional framework. In total, 3643 exosomal proteins (523 hematologic, 3120 solid-tumor) and 627,225 miRNA–target pairs, derived from 350 unique microRNAs, were organized using Gene Ontology, KEGG, and PANTHER annotation. Across cancers, proteins converged on a reproducible core—signaling, transport, cytoskeletal organization, and extracellular interaction—dominated by binding, catalytic, and transporter functions localized to membrane, vesicle, and extracellular compartments. Comparisons between hematologic and solid malignancies revealed both shared cancer-associated functions and context-dependent patterns linked to tissue origin and disease ecology. Together, these findings indicate that integrated protein-and-microRNA profiling offers a useful framework for understanding tumor communication, refining cancer classification, and advancing biomarker discovery, while underscoring that harmonized workflows, independent validation, and mechanistic follow-up remain necessary before descriptive enrichment outputs can support clinically robust applications. Full article

Background and Clinical Significance: The most common cause of liver toxicity with the use of immune checkpoint inhibitors (ICIs) is autoimmune hepatitis. As most patients with prior viral infections such as hepatitis B and hepatitis C were excluded in trials for the use of ICIs, the safety of ICIs in these patients with active or prior treated hepatitis is unknown. With expanded use of these medications in many malignancies, it is important to understand the risk of viral reactivation with these medications. There are only few case series and reports documenting hepatitis B reactivations with the use of ICIs. Case Presentation: We present a middle-aged woman with a history of treated hepatitis B who presented with metastatic gastric cancer. She was treated with two cycles of 5-FU, oxaliplatin and nivolumab followed by maintenance nivolumab. After 14 months of nivolumab, she developed marked transaminitis and was found to have reactivation of hepatitis B. As autoimmune hepatitis was the initial suspicion, the patient was initiated on prednisone 1 mg/kg with no improvement in transaminases. Due to the significant elevation of HBV DNA, she was diagnosed with hepatitis B reactivation. She was initiated on entecavir with normalization of transaminases and improvement in HBV DNA levels. She was successfully rechallenged with nivolumab with no evidence of recurrent transaminitis or worsening HBV DNA levels. Conclusions: There are case series of HBV reactivation with the use of ICIs. We believe that any patients with known history of HBV should get baseline viral titers prior to initiation of ICIs with serial monitoring of DNA levels. Prospective studies to evaluate risk of reactivation may need to be performed for us to get a better understanding of risks of viral reactivation and potential effects it may have on safety and efficacy of ICIs. Full article

Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy and remains a major contributor to global cancer mortality. In situ vaccination (ISV) holds great potential for HCC therapy. Still, its efficacy is severely limited by intrinsic antigen scarcity and the tumor-associated macrophage (TAM)-mediated inhibition of dendritic cell (DC) maturation and T cell activation. In particular, the M2 TAM-HCC cell crosstalk may further aggravate ISV suppression. Moreover, as an internal organ tumor, HCC requires systemic administration of ISV agents, which often cause severe off-target toxicity. Methods: To address these challenges, we developed secretory phospholipase A2 (sPLA₂)-responsive liposomes co-loaded with the TLR7/8 agonist R848 and the ICD inducer doxorubicin (DOX) via a sequential remote loading method, termed sP-Lips@DR. Results: Incorporation of cholesterol (CHOL) significantly improved DOX encapsulation, and the sequential loading method enabled efficient co-encapsulation of both R848 and DOX. sP-Lips@DR responds to an sPLA₂-overexpressed, mildly acidic microenvironment in HCC, enabling selective drug release. In addition, sP-Lips@DR exhibited sPLA₂-responsive cytotoxicity toward H22 cells and macrophage phenotypic shift. Furthermore, sP-Lips@DR could disrupt the crosstalk between M2-like macrophages and H22 cells in an sPLA₂-responsive manner. Conclusions: Overall, the preparation and in vitro evaluation of sP-Lips@DR demonstrate their potential to enhance ISV efficacy in HCC, providing a solid foundation for future in vivo investigations. Full article

Primary sclerosing cholangitis (PSC) is a rare cholangiopathy strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis. PSC-IBD defines a clinically quiescent but biologically aggressive colitis phenotype, characterized by extensive yet often asymptomatic mucosal inflammation and disproportionately elevated risks of colorectal cancer—approximately 3- to 5-fold higher than in IBD alone—and cholangiocarcinoma (CCA), with IBD comorbidity representing an independent risk factor for hepatopancreatobiliary malignancy. The pathogenesis remains incompletely understood but involves genetic susceptibility, immune dysregulation—including aberrant lymphocyte trafficking and an imbalance between T helper 17 (Th17) and regulatory T (Treg) cells—intestinal barrier dysfunction, and gut–liver axis perturbations involving alterations in the microbiota and bile acid homeostasis. Within the biliary tree, chronic inflammation activates peribiliary glands (PBGs), which harbor stem/progenitor cells. PBG hyperplasia may contribute to periductal fibrosis through Hedgehog signaling and epithelial-to-mesenchymal transition and may represent a key step in PSC-associated cholangiocarcinogenesis. The true burden of PSC-IBD is likely underestimated, as PSC may remain clinically silent for years. Bidirectional screening is therefore essential: all patients with PSC should undergo ileocolonoscopy with biopsies regardless of symptoms, whereas patients with IBD and cholestatic liver biochemistry—particularly elevated gamma-glutamyl transferase or alkaline phosphatase—should undergo magnetic resonance cholangiopancreatography. No medical therapy has demonstrated a clear ability to alter the natural history of PSC, and liver transplantation remains the only definitive treatment for advanced disease. This review integrates current evidence on the epidemiology, pathophysiology, and management of PSC-IBD, critically examining unmet needs in timely diagnosis, mechanistic understanding, and therapeutic development, with particular attention to non-invasive biomarkers, microbiota-directed strategies, individualized risk stratification, and disease-modifying endpoints. Full article

Importance: Chronic liver disease requires sustained engagement with the health system, which co-occurring social and functional risks may disrupt. Whether these risks form reproducible patterns with different mortality associations is uncertain. Objective: To identify social and functional risk patterns among US adults with chronic liver disease and evaluate their associations with all-cause mortality. Design, Setting, and Participants: Nationally representative cohort study of National Health Interview Survey sample adults interviewed from 2011 through 2018 and linked to the National Death Index through 31 December 2019. Participants were aged 18 years or older, eligible for mortality linkage, reported a chronic liver condition, and had no baseline liver cancer. Exposures: Latent class membership derived from 7 binary indicators: poverty, food insecurity, uninsurance, cost-related delayed care, no usual place of care, single-adult household status, and activity limitation. A complete 0- to 7-item count was a secondary exposure. Main Outcomes and Measures: All-cause mortality. Survey-weighted Cox models estimated hazard ratios (HRs) with sequential demographic, clinical, and liver-specific adjustment. Prespecified sensitivity analyses used 20 multiple imputed data sets, sampling-weighted pseudo-likelihood latent class models, complete-case re-estimation, a fixed 5-year horizon, and class-by-age interaction testing. Results: Among 3407 adults (weighted mean age, 54.0 years; 49.4% female), 529 deaths occurred over 17,297.6 person-years (median follow-up, 5.0 years [IQR, 3.0–7.0]). Four classes were retained: low social and access burden (weighted prevalence, 63.1%); functional limitation with financial strain (13.2%); poverty, single-adult household, and functional limitation (15.0%); and uninsurance with major access barriers (8.7%). Compared with the low-burden class, the functional-limitation/financial-strain class had higher adjusted mortality (HR, 1.95; 95% CI, 1.34–2.82; p < 0.001); the other 2 classes did not differ significantly. Sampling-weighted latent class analysis after multiple imputation reproduced 97.2% of modal assignments, and the association persisted with attenuation (HR, 1.55; 95% CI, 1.08–2.22; p = 0.02). Each additional risk was associated with higher mortality (exact count: HR, 1.24 [95% CI, 1.13–1.36]; imputed count: HR, 1.19 [95% CI, 1.10–1.29]). The class-by-age interaction was not significant (p = 0.41). Conclusions and Relevance: Among US adults with self-reported chronic liver disease, social and functional adversity was both cumulative and patterned. A profile combining functional limitation, food insecurity, and cost-related delayed care had the clearest independent mortality association despite largely retained insurance coverage. These profiles are not a validated clinical score, but the findings argue against reliance on any single indicator, particularly insurance status, as a marker of vulnerability. Full article