The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) continues to increase worldwide, partly because of rising rates of obesity and metabolic syndrome. However, a substantial proportion of patients with MAFLD are neither overweight nor obese and are classified as having lean MAFLD. The increasingly recognized phenotype of lean MAFLD challenges the traditional paradigm linking obesity to metabolic risk. Despite a normal body mass index (BMI), lean MAFLD is associated with substantial metabolic dysfunction and a range of extrahepatic manifestations. Evidence from systematic reviews and meta-analyses including more than 10 million individuals indicates that patients with lean MAFLD have metabolic profiles comparable to those of overweight or obese patients with MAFLD, including insulin resistance, dyslipidemia, and hypertension. Importantly, although cardiovascular and cancer-related mortality appear broadly similar across BMI categories, liver-related mortality is generally higher in lean individuals, suggesting disticnt hepatocentric vulnerability. Variation in all-cause mortality estimates is influenced by disease severity, study design, and ethnicity. Important mechanistic factors include genetic susceptibility, sarcopenia, and visceral adiposity. These findings support comprehensive metabolic and hepatic assessment in lean MAFLD beyond BMI-based risk classification. This review examines lean MAFLD as a hepatocentric phenotype with systemic effects beyond BMI.

Hepatocellular carcinoma (HCC) exhibits profound metabolic reprogramming, with enhanced aerobic glycolysis and excess lactate production as defining features. Lactate, once regarded simply as a metabolic byproduct, is now recognized as a powerful epigenetic driver through lysine lactylation, while tumor cells co-opt autophagy to endure metabolic stress. Although traditionally investigated as separate hallmarks of cancer, growing evidence points to their functional intersection. Here, we propose the concept of a coordinated “lactylation-autophagy axis” and clarify its role in remodeling the tumor immune microenvironment. Within this integrated metabolic-epigenetic-proteostatic network, lactate-induced histone lactylation, such as H3K18la, exerts transcriptional control over tumor-associated macrophages, shifting them toward an immunosuppressive M2-like state. Excess extracellular lactate and robust autophagic adaptation cooperate to impair the effector functions of CD8+ T cells and natural killer cells, while providing regulatory T cells with metabolic advantages. We further explore the bidirectional crosstalk within this axis: lactate modulates autophagic flux, potentially through mTOR signaling and non-histone lactylation of autophagy-related proteins (e.g., VPS34, TFEB), whereas autophagy in turn regulates intracellular metabolite pools and lactylation substrates. Notably, several nodes, particularly non-histone lactylation of VPS34, TFEB, and mTOR (K921), have been demonstrated mainly in non-HCC systems; we therefore grade each mechanism as confirmed in HCC, extrapolated from other systems, or hypothetical. This proposed self-reinforcing axis may sustain tumor plasticity, contribute to immune evasion and immunotherapy resistance, and we discuss rational combinatorial strategies—combined targeting of lactate metabolism, lactylation machinery, and autophagic pathways—to sensitize advanced HCC to immune checkpoint blockade.

Metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol–associated liver disease (ALD) are leading causes of chronic liver injury with overlapping clinical and histological presentations. This study evaluated a composite histologic pattern, termed the Alcohol Liver Pathology Signature (ALPS), for potential use in the differential diagnosis of ALD and MASLD and to explore potential clinical and demographic correlates.

In this retrospective diagnostic-accuracy study, we reviewed 292 liver biopsies performed between 2021 and 2023. ALPS comprised five histologic features: ductular reaction, bile stasis, neutrophilic satellitosis, portal inflammation, and advanced fibrosis (stage 3–4). Cases were categorized as absent (0–1 features), partial (2–3 features), or full (4–5 features). ALPS performance was then further evaluated in an independent temporal validation cohort of de-identified, mixed, and blindly reviewed liver biopsies collected between 2024 and 2025.

MASLD was the most common diagnosis (25.3%), whereas ALD accounted for 4.8%. Full ALPS was present in 92.8% of clinically diagnosed ALD cases. In MASLD, individual ALPS features were common, but only 20.3% showed full ALPS, corresponding to 79.7% specificity for distinguishing clinically diagnosed ALD from MASLD. The independent temporal validation cohort showed findings consistent with those of the original cohort. Finally, within MASLD, full ALPS was more frequent in African American than non-African American patients (29.2% vs. 3.8%).

ALPS may serve as a histologic prompt for further assessment of potential alcohol exposure but should not be considered etiologically specific. Prospective validation incorporating objective measures of alcohol exposure is warranted.

Hepatic stellate cell (HSC) activation has traditionally been described as a binary transition from vitamin A-rich quiescent cells to alpha-smooth muscle actin-positive, collagen-producing myofibroblast-like cells. Advances in single-cell RNA sequencing, single-nucleus RNA sequencing, spatial transcriptomics, and chromatin-accessibility profiling now reveal a more complex and dynamic landscape. During chronic liver injury, HSCs can adopt five overlapping activation-associated states characterized by injury sensing, inflammatory signaling, proliferation, extracellular matrix production and contractility, together with a senescent state that represents a possible fate of activated HSCs. These states differ in their molecular markers, spatial distribution, regulatory pathways, and interactions with hepatocytes, liver sinusoidal endothelial cells, macrophages, natural killer cells, and cholangiocytes. Importantly, they are not fixed lineages and may coexist or interconvert during fibrosis progression and regression. This review revisits the classical quiescent-activated framework and proposes a state-based approach for interpreting HSC heterogeneity. We summarize the defining features and translational relevance of six major HSC functional states, discuss their multicellular niches, and highlight the opportunities and limitations of function-selective therapeutic targeting. A reproducible classification that integrates molecular identity, spatial context, and causal function may help refine antifibrotic treatment strategies.

Rising resistance in Helicobacter pylori to metronidazole, clarithromycin, and fluoroquinolones has significantly reduced eradication efficacy. This narrative review explores evidence-based strategies that minimize the impact of antibiotic resistance. Current practical approaches include empirical therapy (EMT), in which regimens are selected without individual susceptibility testing based on local or regional resistance patterns, previous antibiotic exposure, guideline recommendations, and expected effectiveness, and susceptibility-guided therapy (SGT), which avoids antibiotics to which the infecting strain is resistant. EMT does not simply exclude every antibiotic with a high resistance prevalence because regimen-level efficacy may remain high despite resistance to one component. When susceptibility testing is unavailable, optimized 14-day bismuth quadruple therapy is a guideline-preferred empirical regimen and can remain effective despite metronidazole resistance with adequate dosing and treatment duration. Rifabutin-based triple therapy provides an additional empirical or rescue option for selected patients without penicillin allergy. SGT is not universally superior to well-selected EMT, but may improve eradication rates in selected populations, particularly in settings with high clarithromycin resistance or where rapid molecular testing is available. However, susceptibility testing may be time-consuming, costly, and limited to only a few antibiotics. Emerging approaches include potassium-competitive acid blockers (PCABs), antimicrobial stewardship, probiotics, N-acetylcysteine, nanomaterial-based drug delivery, and vaccination. Among these, vonoprazan-based regimens are the most clinically mature. Vonoprazan-amoxicillin dual therapy can reduce exposure to resistance-prone antibiotics, although its use should reflect regional effectiveness, availability, and cost. Other non-antibiotic approaches remain investigational. In conclusion, management should move from undifferentiated empirical regimen selection toward risk-stratified precision treatment. Locally validated EMT remains appropriate when susceptibility testing is unavailable, whereas SGT should be prioritized after treatment failure or in patients at high risk of resistance. Rifabutin-based and vonoprazan-amoxicillin therapies provide additional options according to treatment history, penicillin allergy, regional evidence, and accessibility.

Despite the 2012 Berlin definition standardizing acute respiratory distress syndrome (ARDS) diagnosis, pharmacological therapies have consistently failed in phase 3 trials, partly reflecting the syndrome’s profound biological heterogeneity. We synthesize evidence on ARDS subphenotyping to evaluate prospects for precision medicine. This narrative review was informed by targeted searches of PubMed/MEDLINE, Embase, and Web of Science from database inception through February 2026, supplemented by an updated PubMed/MEDLINE search through September 2026. Representative clinical trials, multicenter cohorts, mechanistic studies, and methodological reports were selected to support a critical synthesis of ARDS subphenotyping, its therapeutic implications, and barriers to clinical translation. Hyperinflammatory and hypoinflammatory subphenotypes—originally identified using plasma biomarkers (IL-6, IL-8, and soluble tumor necrosis factor receptor 1) in the ARMA and ALVEOLI cohorts—demonstrate reproducible differences in mortality, with worse outcomes in the hyperinflammatory subphenotype, and have shown potential treatment-effect heterogeneity in secondary analyses. Approximately 30%–35% of patients exhibit the hyperinflammatory profile, characterized by greater vasopressor requirements and organ failure. Radiological phenotypes (focal versus non-focal) on computed tomography imaging have been associated with differences in lung recruitability and physiological responses to ventilatory interventions, although the LIVE trial did not demonstrate an overall survival benefit from morphology-guided ventilation. Recent multi-omics studies (transcriptomic, proteomic, and metabolomic) reveal distinct endotypes involving dysregulated innate immunity, endothelial activation, and aberrant coagulation. Machine learning algorithms, particularly unsupervised clustering and deep learning-based computed tomography radiomics, have been investigated for more rapid phenotyping, but reported performance varies by task, cohort, and validation design. However, prospective, phenotype-guided randomized trials remain limited. Subphenotype stratification offers a mechanistically grounded framework for re-evaluating therapies that were ineffective in unselected populations and for investigating phenotype-informed ventilatory strategies. Clinical implementation requires standardized, bedside-compatible biomarker panels and definitive trials demonstrating that phenotype-specific interventions improve patient-centered outcomes.

Extracorporeal treatment (ECTR) is used in selected severe poisonings to enhance toxin elimination and, in some cases, provide temporary organ support. Modalities include intermittent hemodialysis, continuous renal replacement therapy, and sorbent-based hemoperfusion or hemoadsorption, each with distinct mechanisms and toxicokinetic implications. This narrative review summarizes modality-specific and toxin-specific evidence, operational treatment characteristics, patient-centered and toxicokinetic outcomes, safety considerations, and scenarios in which ECTR should be withheld, and proposes a practical five-step bedside algorithm. Sources were identified through targeted searches of PubMed/MEDLINE and Google Scholar, supplemented by Extracorporeal Treatments in Poisoning (EXTRIP) consensus documents, reference-list screening, and author expertise. The evidence base varies substantially across toxins. For several pharmaceutical poisonings, EXTRIP provides the most actionable guidance on indications, preferred modality, and stopping criteria, while recommending against ECTR for digoxin and methotrexate. Outside these consensus-guided settings, the largest experience with sorbent therapies concerns paraquat and organophosphorus/carbamate poisoning, although the literature is regionally concentrated and predominantly observational. In paraquat poisoning, hemoadsorption-containing strategies have been associated with improved survival in observational cohorts, while pharmacokinetic studies support early and repeated treatment in selected patients because of ongoing toxin removal and post-treatment rebound. In organophosphorus/carbamate poisoning, comparative studies suggest possible benefit in severe presentations, but certainty remains low. In diquat poisoning, recent reports emphasize concentration-directed extracorporeal strategies. Evidence for other toxins is largely limited to feasibility, toxin removal, and case-based experience. ECTR should therefore be regarded as a toxin-specific therapeutic toolbox rather than a uniform intervention. Where available, EXTRIP recommendations should guide practice. Otherwise, modality selection should integrate toxicokinetic plausibility, clinical severity, feasibility, and safety. Prospective studies using standardized prescriptions and clinically meaningful endpoints are needed.