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.
MicroRNAs (miRNAs) have been studied in cutaneous T-cell lymphoma (CTCL) for more than 15 years, revealing oncogenic and tumor-suppressive networks, the JAK/STAT-miRNA signaling circuit, diagnostic classifiers, and therapeutic miRNA targeting (Cobomarsen, targeting miRNA-155). Yet, no miRNA diagnostic has reached clinical practice. We synthesize the CTCL miRNA literature and argue that translation has stalled as a result of 2 interrelated limitations-methodological and biological-including reliance on bulk-tissue profiling and the intrinsic miRNA biology, including modest regulation of multiple pathways. Future strategies encompassing single-cell and subclone profiling, targeted anti-miRNA delivery, multiomics integration, miRNA network remodeling, multicenter validation, and artificial intelligence-driven bioinformatics may herald a golden renaissance for miRNAs.
Autoimmune skin diseases impose substantial morbidity despite therapeutic advances, with current treatments requiring lifelong immunosuppression without eliminating pathogenic immune responses. Chimeric antigen receptor (CAR) T-cell therapy is a promising approach to achieve durable remission through the targeted elimination of immune cells followed by immune reconstitution. This review examines CAR-T therapy in dermatologic autoimmunity, discussing CD19- and B-cell maturation antigen-targeted approaches alongside precision strategies such as chimeric autoantibody receptor T cells. Early clinical data demonstrate drug-free remissions with favorable safety profiles, although longer follow-up and randomized trials are needed to establish durability and comparative effectiveness before CAR-T therapy can fulfill its potential.
