Let H=(V,E) be a hypergraph with n vertices and m edges. A subset S⊆V is an eliminating vertex feedback set of H if Image 1 contains no cycles, and we denote its minimum cardinality by Dc(H). Analogously, a subset A⊆E is called an eliminating edge feedback set of H if Image 2 contains no cycles, and its minimum cardinality is denoted by Dc′(H). In this paper, we establish upper bounds for both parameters. For the vertex version, we prove that Dc(H)≤(k−1)n−m+1 for any k-regular connected hypergraph H. For the edge version, we show that: (i) Dc′(H)≤n/2 for any hypergraph H; (ii) Dc′(H)≤n/4 for any 2-regular hypergraph H with girth at least 4; and (iii) Dc′(H)≤n/3 for any 2-regular or 3-regular hypergraph H with girth at least 3. Furthermore, we characterize the extremal regular hypergraphs attaining these upper bounds. Based on our proofs, we also design combinatorial algorithms for computing the eliminating feedback numbers.
We propose and study the diversity-aware l-centrum (div-l-centrum) problem, where we are given a set of clients and a set of facilities in a metric space, integers k and l, and r[i] (i∈[t]) for each facility group. The diversity constraints refer to the requirement that each group must include at least r[i] open facilities. The goal is to find a subset of facilities of size at most k so as to minimize the sum of the l largest distances from a client to its nearest open facility, while satisfying the diversity constraints. As our main contribution, we provide a fixed-parameter tractable (1+2/e+ε)-approximation algorithm that improves upon the previous (3+ε) for the div-l-centrum problem, based on a combination of leader selection, coreset construction and submodular optimization techniques.
For a graph G=(V,E), let Gn denote the graph whose vertex set is Vn in which two distinct vertices (u1,u2,…,un) and (v1,v2,…,vn) are adjacent, if and only if for all 1≤i≤n, either ui=vi or uivi∈E. The Shannon capacity of G is defined to be c(G)=supnα(Gn)1n, where α(Gn) is the maximum size of an independent set of vertices in Gn. In this paper, we prove that α(G⊠H)=α(G)α(H) for any connected graph G and connected bipartite graph H. We prove that for any graph G and bipartite graph H (or point-symmetric H which satisfies that α(H)ω(H)=|V(H)|), if the Shannon capacity of G is finite, then the Shannon capacity of G⊠H is finite. The r-color Ramsey number R(k1,…,kr) is defined as the smallest positive integer N such that in every edge-coloring of KN by r colors there is a monochromatic copy of Kki in color i for some 1≤i≤k. In 2002, Robertson obtained a lower bound on the r-color Ramsey number R(k1,k2,…,kr). We establish a new lower bound on the r-color Ramsey number of graphs. From this, we can improves the theorem of Robertson for some cases. A specific result improves the inequality R(7,9,7,7)≥5384 to that R(7,9,7,7)≥64261.
Deoxysphingolipids (dSLs) are atypical sphingolipids that accumulate in several pathological settings, yet their impact on hematologic malignancies is poorly understood. Here, we investigate the pathways and mechanisms of deoxysphinganine (dSA) cytotoxicity in lymphoma cells and its potential as a therapeutic agent. dSA exhibited markedly greater cytotoxicity than canonical sphingoid bases in lymphoma cell lines, yet induced only cytostatic effects in normal human T cells, indicating a therapeutically exploitable window. Inhibition of ceramide synthase blocked the generation of deoxy(dihydro)ceramides, prevented mitochondrial depolarization, caspase activation, ER stress, and DNA damage, establishing CerS-dependent deoxysphingolipids as essential mediators of dSA-induced death. Mechanistically, dSA engaged a mitochondrial apoptotic pathway, with DNA damage occurring downstream of mitochondrial permeabilization and caspase activation, while PERK-driven ER stress occurred in parallel and was dispensable for cytotoxicity. Subtype-specific engagement of ER stress and DNA damage further suggests that dSL signaling is shaped by lineage context. The differential sensitivity between malignant lymphoid cells and normal T cells, together with the central role of CerS-derived deoxy(dihydro)ceramides, highlights deoxysphingolipid metabolism as a druggable vulnerability in lymphoma. These findings support further exploration of dSA-based strategies and targeted modulation of dSL synthesis as a novel therapeutic avenue for non-solid hematologic malignancies.
Whether the fecal metabolome differs according to intensive low-density lipoprotein cholesterol (LDL-C) target achievement among statin-treated patients is unclear. In this cross-sectional study, 124 statin-treated adults with chronic disease were stratified by fasting LDL-C into a target-achieved group (< 70 mg/dL, n = 52) and a target-not-achieved group (≥ 70 mg/dL, n = 72). Stool samples were profiled by untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry, and multivariable models adjusted for age, sex, chronic kidney disease, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were used to identify metabolites independently associated with target achievement. Statin dose, treatment duration and glucose-lowering therapy were also compared between the groups. Paired 16S rRNA gene sequencing data available for a subset (n = 86) were used for integrative correlation and network analyses. Partial least-squares discriminant analysis showed separation between the two groups. Eight annotated metabolites-glutamine, glutamate, phenylalanine, N-acetyl-L-phenylalanine, L-methionine, N-acetyl-L-methionine, lysine, and N-methyl-D-aspartic acid, predominantly amino acids and their derivatives-were present at lower fecal levels in participants who achieved the LDL-C target. Metabolite set enrichment analysis implicated amino acid and nitrogen metabolism, and multiomics network analysis identified an Anaerotruncus-centered amino acid module with high degree centrality. In conclusion, LDL-C target achievement under statin therapy was associated with a coherent "low fecal amino acid" signature and an Anaerotruncus-linked microbe-metabolite hub. These findings suggest that intestinal nutrient handling and gut microbial amino acid metabolism may contribute to variability in LDL-C response, and they warrant prospective mechanistic evaluation.
Metabolic dysfunction-associated liver disease (MASLD) arises from the accumulation of triglycerides within the liver. MASLD can advance to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. Monoacylglycerol acyltransferase 2 (MOGAT2) is essential for triglyceride synthesis and plays a significant role in regulating lipid metabolism. Here, we demonstrate the ability of a new human MOGAT 2 inhibitor, VB-85387, to inhibit the development of MASLD/MASH and further define its effects on the key metabolic pathways that progress MASH development. MASLD/MASH was induced using a methionine, choline-deficient diet (LMCD) or by streptozotocin treatment combined with high fat diet feeding (STAM-HFD). VB-85387 significantly mitigated the severity of MASLD and reduced signs of MASH in mice subjected to these two distinct diets. VB-85387-treated mice exhibited decreased fibrosis, evidenced by reduced hepatic triglyceride concentrations, hydroxyproline levels, and collagen deposition. NAS scores were consistently lower in VB-85387-treated mice across both models. VB-85387-treated mice showed induced PPARα signaling and reduced SREBP transcription, demonstrating a likely role for VB-85387 in regulating lipogenesis and fatty acid β-oxidation. STAM-HFD treated mice showed lower NF-κBp65 activation, which was associated with lower TNFα expression. IL-1β and IFNβ levels were also both reduced, suggesting VB-85387 can reduce pro-inflammatory pattern recognition receptor signaling. In addition, treatment suppressed IL-4/IL-6-dependent JAK activation. Overall, VB-85387 inhibited MASLD development by reducing liver triglyceride levels, fibrosis, and meta-inflammatory signaling. VB-85387 was as effective or superior to the MOGAT2 inhibitor phase I clinical trial drug BMS-963272 in reducing MASLD and fibrosis. VB-85387 has considerable potential for developing therapeutics targeting MASLD/MASH.
Glioma represents one of the most aggressive tumors in the central nervous system, with clinical management facing significant challenges including high recurrence rates and therapeutic resistance. Ferroptosis, an iron-dependent form of cell death, holds potential for glioma treatment, yet tumor cells frequently develop evasion mechanisms. This study elucidates the molecular mechanisms by which hypoxic microenvironment confers ferroptosis resistance in glioma cells, focusing on the pivotal role of the HIF-1α/SREBP1 signaling axis and its downstream effectors FASN and SCD1. Our experimental results demonstrate that hypoxic conditions significantly upregulate HIF-1α expression and confer resistance to RSL3-induced ferroptosis. Mechanistic studies reveal that HIF-1α promotes SREBP1 activation, which subsequently upregulates FASN and SCD1 expression to suppress lipid peroxidation.Furthermore, the HIF-1α-specific inhibitor PX-478 effectively reverses hypoxia-induced ferroptosis resistance and significantly enhances tumor cell sensitivity to ferroptosis inducers. In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies.
BACKGROUND:Lipoprotein(a) [Lp(a)] reflects inherited atherothrombotic risk, whereas the C-reactive protein-triglyceride-glucose index (CTI) integrates systemic inflammation, triglyceride-related lipid disturbance, and glucose-related metabolic stress. Their individual and joint association with angiographic coronary lesion burden in acute coronary syndrome (ACS) remain incompletely defined. We examined whether CTI complements Lp(a) in characterizing coronary lesion burden in ACS. MATERIALS AND METHODS:This retrospective, single-center study included 2,836 consecutive patients with ACS who underwent coronary angiography. Coronary lesion burden was assessed using continuous Gensini score, a high Gensini score, and multivessel disease (MVD). Multivariable regression, restricted cubic spline analyses, CTI-stratified analyses, incremental receiver operating characteristic analyses, and internally validated machine-learning analyses with SHAP interpretation were performed. RESULTS:Higher Lp(a) and CTI level were both associated with greater coronary lesion burden. Compared with Lp(a) <75 nmol/L, Lp(a) ≥175 nmol/L was associated with high Gensini score (OR, 1.51 [95% CI, 1.17-1.96]) and MVD (OR, 1.69 [95% CI, 1.27-2.26]). Each 1-SD increase in CTI was associated with high Gensini score (OR, 1.47 [95% CI, 1.35-1.60]) and MVD (OR, 1.18 [95% CI, 1.08-1.28]). Among inflammatory-lipid indices, CTI showed the most consistent associations and provided the largest numerical incremental discrimination beyond Lp(a). The associaton between ver high Lp(a) and coronary lesion burden was more pronounced at higher CTI levels, particular for MVD. Machine-learning analyses further supported the relevance of both CTI and Lp(a). CONCLUSIONS:In patients with ACS, higher Lp(a) and CTI level were associated with greater angiographic coronary lesion burden. CTI may complement Lp(a) by capturing inflammatory-metabolic status, supporting their joint assessment for more refined characterization of lesion-burden risk in ACS.
Lipoprotein metabolism is significantly different between mice and humans thus making it difficult to model disorders of human lipid metabolism in transgenic mice. Systemic lipoprotein metabolism is predominantly governed by hepatocytes, and mice with humanized livers display human-like lipid profiles. Here we report a highly efficient method to knock out genes in human hepatocytes while retaining their ability to repopulate immune deficient rodents. As proof-of-principle Fah deficient, immune compromised mice were repopulated with Apolipoprotein B (APOB) knockout human hepatocytes. Mice humanized with knockout cells recapitulated typical features of human hypobetalipoproteinemia. We conclude that at least some human lipid metabolism disorders can be modeled in liver chimeric mice using human knockout hepatocytes.
In this paper we study the computational power of certain classes of dynamical systems defined by the iteration of piecewise rational affine maps on the compact set [0,1]n as a model of computation over the real numbers. To achieve this aim we use symbolic dynamics to study the dynamics of this class of piecewise rational affine maps and in the process introduce multidimensional generalized shifts, which are an extension of the generalized shift of Moore to higher dimensional spaces. We show that multidimensional generalized shifts are not equivalent (conjugate) to (one-dimensional) generalized shifts.We then establish that computable analysis, which allows to extend computability based on Turing machines to real numbers, is computationally equivalent to multidimensional generalized shifts, both at a computability and at a computational complexity (polynomial time) level. This implies that a certain class of dynamical systems defined by the iteration of rational piecewise affine maps on the unit ball can thus compute any function computable over the real numbers in the computable analysis sense.These results highlight that several distinct models of computation over the real numbers, such as computable analysis, Claude Shannon's General Purpose Analog Computer, certain classes of piecewise rational affine maps, and the generalized shift, are all computationally equivalent.
High-altitude polycythemia (HAPC) remains prevalent among Tibetans despite genetic adaptations, including EPAS1/HIF2A. Excessive erythrocytosis elevates blood viscosity and increases cardiopulmonary risk, yet erythrocyte metabolic and membrane-lipid mechanisms of HAPC and of therapeutic erythrocytapheresis (TE) remain incompletely defined. We conducted integrated metabolomic and lipidomic profiling of washed erythrocytes from HAPC patients and non-HAPC (NHAPC), and from HAPC patients after TE. Relative to NHAPC, HAPC showed coordinated erythrocyte remodeling spanning amino acid and purine metabolism together with membrane phospholipid and lipid structure (unsaturation and chain length) changes. The disease contrast was multiomic, whereas the acute post-TE contrast was lipid dominant, consistent with apheresis acting primarily through erythrocyte removal. K-means stratification revealed clinically meaningful TE response heterogeneity, but erythrocyte omics did not define stable responder subtypes. These findings point to erythrocyte membrane lipids as a persistent molecular feature of HAPC and of the acute TE response.
Clinically, acute kidney injury (AKI) is one of the most frequent complications of Naja atra (N. atra) envenomation, primarily attributed to snake venom phospholipase A2 (SVPLA2). Although the SVPLA2 inhibitor varespladib shows great therapeutic promise, the underlying mechanisms remain incompletely understood. Herein, we integrated multi-omics and molecular biology approaches to investigate the critical role of SVPLA2 in N. atra venom-induced AKI, as evidenced by pharmacological inhibition with varespladib. Proteomic profiling identified HRAS and CCND1 as key mediators of SVPLA2-induced nephrotoxicity. Mechanistically, SVPLA2 disrupts lipid raft integrity, impairing HRAS palmitoylation-dependent plasma membrane localization and GTPase activity. This defect suppresses phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, causing apoptosis and cell cycle arrest in renal tubular epithelial cells, enforced activation of PI3K-AKT signaling effectively rescued cells from injury. Beyond direct cytotoxicity, SVPLA2 profoundly remodels the renal immune microenvironment. SVPLA2 enhances glycolysis by upregulating hexokinase 2 (HK2) while suppressing fatty acid oxidation through downregulation of carnitine palmitoyltransferase IA, thereby metabolically driving M1 polarization. This metabolic shift impairs macrophage efferocytosis and sustains inflammatory injury. HK2 knockdown reverses these effects in macrophages. Taken together, this study reveals a dual epithelial-immune mechanism by which SVPLA2 activity critically contributes to N. atra venom-induced AKI, as evidenced by pharmacological inhibition with varespladib. These findings highlight PI3K-AKT signaling and HK2 as potential therapeutic targets for N. atra-triggered AKI. Supplementary key words.
Pancreatic lipase is the major enzyme responsible for breaking down dietary triglycerides in the intestines. A previous report suggested that intestinal angiopoietin-like 4 (ANGPTL4) might serve as an endogenous inhibitor of pancreatic lipase and thus regulate fat absorption. As ANGPTL4 expression is reportedly induced by high-fat-diet feeding, we hypothesized that induction of ANGPTL4 by a high-fat diet would lead to an increased inhibition of pancreatic lipase, less breakdown of dietary triglycerides, and ultimately a reduced rate of postprandial triglyceride absorption. To test this hypothesis, we generated intestinal epithelial cell-specific ANGPTL4 knockout mice, fed them diets with varying levels of fat, and measured postprandial triglyceride absorption and intestinal triglyceride lipase activity. As we hypothesized, we found that chronic high-fat feeding reduced the rate of postprandial triglyceride absorption in mice. However, this regulation of postprandial triglyceride absorption appeared to be largely independent of ANGPTL4, as similar decreases were observed in both wild-type and intestinal epithelial cell-specific ANGPTL4 knockout mice. We conclude that there is mechanism by which chronic high-fat feeding reduces the rate of secretion of dietary triglycerides into the circulation, but that this mechanism does not require intestinal ANGPTL4.
Weight rebound remains the core challenge in the long-term management of obesity. Although current mechanistic understanding mainly focuses on physiological adaptations, the role of biomechanical factors remains largely unexplored. This study aims to investigate the contribution of lysyl oxidase (LOX)-mediated adipose tissue (AT) stiffening to the process of weight rebound. Our clinical analysis first established a correlation among obesity, elevated AT stiffness, and higher LOX levels. We then demonstrated that the weight rebound model mice displayed accelerated lipid accumulation and worsened metabolic functions. Importantly, AT stiffness dynamically increased during obesity, failed to normalize after weight loss due to persistent fibrosis, and reached its highest level during the regain stage. LOX expression followed an identical temporal pattern, showing a strong positive correlation with tissue stiffness. Mechanistically, mimicking a high-stiffness microenvironment in vitro promoted adipocyte differentiation and lipid accumulation in a LOX-dependent manner. Crucially, pharmacological inhibition of LOX in vivo significantly attenuated the rate of weight rebound. Our findings provide supportive evidence that LOX-mediated AT stiffening creates a pro-adipogenic mechanical microenvironment that contributes to accelerated weight rebound and metabolic deterioration, highlighting the LOX-stiffness axis as a potential therapeutic target for preventing weight rebound.
Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory and antioxidant properties. We therefore hypothesized that CBD may modulate atherosclerosis development; however, preclinical evidence remains limited and sex-specific effects are poorly understood. Male and female apolipoprotein E-deficient (ApoE-/-) mice were fed a Western-type diet for 12 weeks and received either a CBD nanoemulsion (≈80 mg/kg/day) or vehicle via drinking water. Atherosclerosis was quantified by aortic plaque area, and lipidomic profiling together with aortic root proteomics were used to characterize CBD-induced metabolic changes. CBD treatment significantly reduced aortic plaque area in male but not female mice, without affecting body weight or standard serum lipid parameters. Untargeted lipidomics revealed sex-specific remodeling of the serum lipidome in males, including enrichment of ether-linked triacylglycerols, a class connected to ether-lipid metabolism; however, no lipid class emerged as a robust correlate of plaque burden. Proteomic analysis identified male-specific downregulation of mitochondrial oxidative and stress-related pathways, consistent with reduced vascular oxidative burden. In vitro, CBD attenuated oxLDL-induced oxidative stress and inflammatory activation in endothelial cells, supporting a direct vascular effect. CBD elicited no comparable molecular or plaque changes in females. Collectively, chronic CBD administration exerts a sex-dependent, anti-atherogenic effect in male ApoE-/- mice, associated with downregulation of mitochondrial oxidative metabolism and attenuation of endothelial oxidative and inflammatory activation, alongside remodeling of ether-linked lipid metabolism whose contribution to plaque protection remains to be established. These findings highlight the importance of incorporating sex-specific responses in future mechanistic and translational studies of CBD in atherosclerosis.
CREST superfamily members are a series of multi-transmembrane proteins conserved across a wide range of species. There are approximately 20 members in mammals. CREST superfamily members have been assigned various functions, including those of receptors, transporters, enzymes, and membrane fusion factors. Recent functional and structural analyses of CREST superfamily members have revealed that all members possess a structure resembling an enzymatic active site that catalyzes hydrolysis reactions. Furthermore, it is becoming increasingly clear that they interact with various membrane lipids and are involved in lipid metabolism. This review summarizes current knowledge of the structure and function of each CREST superfamily member and explores their potential as lipid-metabolizing enzymes.
Cardiolipin (CL) is a unique dimeric phospholipid essential for mitochondrial integrity and stress signaling. While most CL is present in the inner mitochondrial membranes (IMM), CL can be exposed to the outer mitochondrial membrane (OMM) under specific physiological and pathological conditions; however, the mechanisms regulating its metabolism at the OMM are poorly defined. Based on its striking structural similarity to cardiolipin deacylase 1 protein (Cld1p), a yeast CL hydrolase, we hypothesized that α/β-hydrolase domain-containing protein 4 (ABHD4) functions as a mammalian CL hydrolase. We identified two isoforms of mouse ABHD4 arising from alternative splicing: ABHD4-1 localizes to lipid droplets, whereas ABHD4-2 selectively targets mitochondria and is enriched in oxidative tissues. We demonstrate that ABHD4 selectively hydrolyzes CL in vitro, producing monolysocardiolipin and dilysocardiolipin. Site-directed mutagenesis identified catalytic serine residues as essential for enzymatic activity in ABHD4 and its Drosophila homolog, Pummelig. In contrast to Cld1p, which resides in the IMM, topological analyses indicate that ABHD4-2 and Pummelig-2 localize to the cytosolic face of the OMM, a conserved orientation that suggests a function distinct from classic acyl chain remodeling of CL. In brown adipocytes, ABHD4-2 overexpression reduces mitochondrial membrane potential in an activity-dependent manner. In silico analyses further reveal conservation of the catalytic triad across yeast, insect, and mammalian orthologs, supporting an evolutionarily conserved role for this enzyme family in CL metabolism. Together, these findings identify ABHD4-2 as an OMM-localized phospholipase with preferential CL hydrolase activity and define an isoform-specific pathway linking CL metabolism to mitochondrial stress responses.
Antiphospholipid syndrome (APS) is an autoimmune thrombophilia diagnosed by established clinical and serological criteria, distinguishing it from other causes of venous thromboembolism (VTE). This study investigated whether VTE is associated with plasma lipidome changes and whether an APS-specific lipid signature can be identified. We performed quantitative mass spectrometry-based lipidomics on plasma from healthy controls (n = 16), patients having VTE without APS (n = 16) and triple-positive APS patients (n = 17), profiling 224 lipid species across all major classes. Ceramide species (Cer 18:1;O2/16:0,/18:0,/20:0 and/26:0) and the Cer 18:0/Cer 24:0 ratio were elevated in both VTE groups relative to healthy controls, consistent with a shared thrombotic state. To identify APS-specific changes, LASSO logistic regression defined a minimal discriminating lipid panel. PE 40:5 (elevated 1.69-fold in APS), SM 43:2;O2 and PC O-34:2 (both reduced by 21%-24%) were combined into a parameter-free composite score that discriminated APS from VTE without APS with an AUC of 0.857. PE 40:5 has previously been associated with cardiovascular inflammatory activation, whilst reduction of PC O-34:2 may reflect increased conversion to platelet-activating factor and/or plasmalogen consumption under the pro-inflammatory conditions of APS. The co-occurrence of elevated ceramides and decreased SM 43:2;O2 in APS raises the hypothesis of enhanced acid sphingomyelinase activity driving sphingomyelin-to-ceramide conversion. Prospective validation in larger cohorts is warranted to assess its utility as a complement to serological APS diagnostics. In conclusion, despite the limited sample size, plasma lipidomics identifies a three-lipid composite score that discriminates APS from VTE without APS.
In metabolic dysfunction-associated steatohepatitis (MASH), abnormalities in posttranslational modification (PTM) are both a consequence of the pathological process and a driving force for disease progression. Therefore, this study intends to characterize the PTM features (acetylation, lactylation, and phosphorylation) of MASH, which will provide a crucial theoretical basis for the diagnosis and development of new targets for MASH. In this study, protein/modification profiles of clinical liver tissues from Normal and MASH were analyzed by LC-MS to identify differentially expressed proteins (DEPs) and differentially modified proteins with acetylation, lactylation, and phosphorylation. This study found that acetylation and lactylation occurred mainly in K, whose upstream and downstream amino acids consisted of A, G, K, R, and V. Phosphorylation occurred mainly in S and T, whose upstream and downstream ones consisted of D, E, P, R, and S. Proteomics with ordinary, acetylation, lactylation, and phosphorylation identified 468, 433, 434, and 1,471 DEPs/differentially modified proteins, respectively, which mainly regulate cytoskeleton, immunity, proliferation, oxidative stress, inflammatory cascades, and various metabolisms (sugars, amino acids, lipids, and carbon). CMKLR1, CYP2E1, GLRX, and XRCC1 were identified as key regulators in the shared DEPs of ordinary proteomics and modification proteomics. Notably, the differences in expression of the four proteins in clinical liver tissues from Normal and MASH were consistent with the proteomics results. In conclusion, this study systematically revealed the protein expression profiles associated with acetylation, lactylation, and phosphorylation in MASH, and highlighted that modifications of CMKLR1, CYP2E1, GLRX, and XRCC1 represent potential therapeutic targets for MASH.
