Biology subjects

Lyssiotis, C. A.

Publications and source records attributed to Lyssiotis, C. A..

At least 19 recordsLinked to original sources

bioRxiv2026

A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.

cancer biology↗

bioRxiv2026

Redox imbalance dictates dependence on GOT1 versus GOT2 for rod photoreceptor health during aging and stress

Photoreceptor (PR) loss causes vision loss in many blinding diseases, and effective therapies to prevent this cell loss are lacking. Aspartate aminotransferases (GOTs), located in the cytosol (GOT1) and mitochondria (GOT2), are key components of the malate-aspartate shuttle, which transfers reducing equivalents from cytosol to mitochondria. Previous work has implicated the GOTs as potential modulators of blinding retinal disease. To determine the roles of GOT1 and GOT2 in rod PRs, we generated rod PR-specific Got1 or Got2 conditional knockout mice (Got1 or Got2 cKO). We previously showed that Got1 cKO causes PR degeneration and is accompanied by NADH accumulation and a decreased retinal NAD+/NADH ratio. Here, we show that NADH oxidation via metabolic or genetic means prolongs PR survival in Got1 cKO animals, implicating NADH accumulation, or reductive stress, as a key driver of PR degeneration. In contrast, Got2 cKO causes minimal PR degeneration and alterations in retinal NADH and the NAD+/NADH ratio that oppose reductive stress. Interestingly, GOT2, but not GOT1, is decreased in multiple models of PR degeneration, including retinal detachment (RD) where the NAD+/NADH ratio favors a reductive state. Notably, loss of Got2 in PRs demonstrates a neuroprotective effect after experimental RD suggesting decreased GOT2 expression may be part of a stress response to promote PR survival. Overall, this study illustrates the differential dependence on the GOTs for PR health, provides evidence that an overly reductive environment is detrimental to PR survival, and identifies GOT2 as a novel therapeutic target with potentially broad application in blinding diseases.

neuroscience↗

bioRxiv2026

Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine

As solid tumors progress, the tumor microenvironment (TME) becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of the immune checkpoint blockade. However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid-neutrophil-adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils to generate adenosine via PPAR activation, leading to T-cell suppression. Using AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.

cancer biology↗

bioRxiv2026

Synthetic Immunological Niche Reveals Early Immune Dysregulationand Stratifies Therapeutic Response in Type 1 Diabetes

In Type 1 Diabetes (T1D), disease onset and response to immunotherapy vary widely among individuals, reflecting heterogeneous stage-specific immune dysregulation that remains undefined. To investigate this heterogeneity, we engineered a microporous polycaprolactone scaffold that forms a synthetic immunological niche (IN) upon subcutaneous implantation, enabling in vivo capture of systemic immune dysregulation. In non-obese diabetic (NOD) mice, longitudinal transcriptomic profiling of IN-infiltrating cells identified early-stage genes relatively enriched for myeloid cells, followed by progressive increases in T cell-associated dysregulation at later stages that distinguished T1D progressors from non-progressors. We derived an early-stage IN-based T1D gene signature capturing immune alterations. The signature stratified NOD progressors from non-progressors as early as 6 weeks of age and was conserved across human T1D datasets, distinguishing T1D from non-diabetic individuals in spleen and pancreatic lymph node samples, but not peripheral blood. Signature-based stratification further revealed enrichment of macrophage-associated TNF- pathways in NOD progressors, validated in human T1D islets. Given heterogeneous response to anti-TNF- therapy, IN profiling identified resistance-associated mechanisms and enabled derivation of a pathway score that prospectively distinguished treatment-sensitive from resistant mice prior to therapy, establishing the IN as a minimally invasive platform for detecting stage-wise immune dysregulation and stratifying immunotherapy response in T1D.

bioengineering↗

bioRxiv2026

Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound metabolic rewiring and a strongly immunosuppressive tumor microenvironment, both of which contribute to poor therapeutic responses. Immunogenic cell death (ICD) represents a potential strategy to overcome immune suppression by coupling tumor cell death to anti-tumor immune activation. Here, we investigated whether targeting amino acid metabolism in PDAC can induce ICD and promote tumor immunity. Through a focused metabolic screen in a panel of syngeneic mouse cancer cell lines, we identified cysteine restriction as a robust inducer of multiple damage-associated molecular patterns (DAMPs) in vitro, hallmark features of ICD. In addition to driving DAMPs, cystine-deprived tumor cells also promoted dendritic cell phagocytosis, maturation, and proinflammatory cytokine production in vitro. Because cysteine deprivation is a known trigger of ferroptosis, we further demonstrated that pharmacologic inhibition of glutathione peroxidase 4 (GPX4) similarly elicited ICD-associated features, which were reversible by the ferroptosis inhibitor Ferrostatin-1. To define additional immune-modulatory signals associated with ferroptosis, we performed metabolomic and lipidomic profiling of cells undergoing, but not yet committed to, ferroptotic death. These analyses revealed selective release of immunosuppressive metabolites and oxidized phospholipids. Consistent with this, conditioned media from ferroptotic cells impaired CD8 T cell proliferation and cytotoxicity in vitro. Thus, together our results indicated that the induction of ferroptotic immunogenic cell death led to the release of both pro- and anti-inflammatory signals. Subsequent analysis in vivo revealed that ferroptotic tumor cells predominantly contributed to a tumor-protective environment. In particular, tumors inoculated with ferroptotic cells were enriched with immunosuppressive myeloid cells and exhibited reduced populations of tumor-infiltrating CD8+ T cells. Further investigation using immune compromised mice suggested that ferroptotic cells may suppress both adaptive and innate immune responses. Collectively, these results underscore the complex and highly context-dependent effects of ferroptosis on tumor immunity, highlighting the critical importance of in vivo models to determine true immunogenic potential within the tumor microenvironment.

cancer biology↗

bioRxiv2025

Aspartate Transaminases Are Dispensable for Pancreatic Development and Pancreatic Cancer Progression

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States. This is due in part to the limited availability of effective treatment options for patients, highlighting a significant need for new targets and approaches. Deregulated metabolism is a hallmark feature of PDA that has gained attention as a promising inroad for therapy. The aspartate transaminases (glutamate oxaloacetate transaminases, cytosolic GOT1 and mitochondrial GOT2) have several important metabolic functions, including maintaining energy and redox balance and generating aspartate, an essential building block in protein and nucleotide biosynthesis. Previous studies of GOT proteins in preclinical tumor transplant models have yielded conflicting results regarding the requirement of GOT1 and GOT2 for PDA tumor growth. To assess the role of GOT proteins in tumor development and tumor maintenance, we generated conditional knockout mice for Got1 and Got2 and crossed these into pancreas-specific models. Whereas loss of either Got does not impact pancreas development, double Got1 and Got2 knockout results in markedly reduced pancreas size and cellularity without overtly impacting endocrine or exocrine function. In genetically engineered cancer models, single Got loss does not impact lesion formation, tumor size, animal survival, or the composition of the tumor microenvironment. Identical results were also observed in orthotopic allograft mouse models. Together, these findings add to a growing body of work illustrating the adaptability of metabolism in cancer. They also emphasize the importance of model selection, the use of multiple independent models, and the in vivo context when studying the role of metabolic programs in cancer.

cancer biology↗

bioRxiv2025

Longitudinal Analysis of Matched Patient Biospecimens Reveals Neural Reprogramming of Cancer-Associated Fibroblasts Following Chemotherapy in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). How chemotherapy alters the TME, and whether these changes drive chemoresistance, is poorly understood. We examined matched pre- and post-treatment tissue specimens and found near-universal enrichment of axonal guidance genes in cancer-associated fibroblasts (CAFs) after treatment. These CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrence lesions had the highest prevalence of these CAFs versus primary tumors and untreated metastasis. These CAFs showed elevated non-canonical Wnt mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Our findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising target for this disease. Statement of SignificanceTherapeutic resistance remains a major challenge in pancreatic cancer. Our findings shed light on the changes in the complex tumor microenvironment in response to chemotherapy and identify fibroblasts high in axonal-guidance genes that may drive tumor progression and chemoresistance, thus uncovering a potential avenue for targeting pancreatic cancer.

cancer biology↗

bioRxiv2025

Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia

Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.

cancer biology↗

bioRxiv2025

Reprogramming the Immune Suppressive Tumor Microenvironment in Glioma Enhances the Efficacy of Immune-Mediated Gene Therapy

Gliomas account for ~80% of primary malignant brain tumors. Many CNS WHO grade 2-3 and some grade 4 gliomas harbor mutant isocitrate dehydrogenase 1 (mIDH1), which causes a gain of function mutation (IDH1 R132H) leading to the production of 2-hydroxyglutarate (2HG). Mutant IDH1-induced 2HG, through epigenetic reprogramming elicits an immune-permissive tumor microenvironment (TME). An immunosuppressive mechanism in the glioma TME involves adenosine production via the ectoenzyme CD73. This study investigates mIDH1s influence on CD73 expression and adenosine levels. We demonstrate that mIDH1 glioma cells exhibit reduced CD73 expression, driven by DNA hypermethylation, leading to reduced adenosine levels. Since wtIDH1 gliomas have high CD73 expression, we evaluated CD73 blockade as an immunotherapy target. We show that CD73 inhibition used as monotherapy, did not improve survival in wtIDH1 glioma-bearing mice. However, when combined with immune-stimulatory Ad-TK (adenoviral vectors encoding herpes simplex virus thymidine kinase) and Ad-Flt3L (adenoviral vectors encoding FMS-like tyrosine kinase 3 ligand) gene therapy, CD73 blockade significantly enhanced therapeutic efficacy and increased anti-glioma effector T cell activity. These findings reveal that CD73 inhibition used in combination with immune stimulatory Ad-TK/Ad-Flt3L gene therapy may be an effective treatment for wtIDH1 gliomas, which could be readily translated to the clinical arena.

cancer biology↗

bioRxiv2025

Iron addicted colorectal cancers exploit Heme-Complex II axis to resist oxidative cell death

Colorectal cancer (CRC) cells are addicted to iron, which fuels nucleotide synthesis, mitochondrial respiration, and rapid proliferation. Yet paradoxically, high intracellular iron is cytotoxic to most other cells, raising the question of how CRC cells tolerate and exploit iron-rich environments. One pathway thought to mediate iron toxicity is ferroptosis, an iron-dependent form of cell death. However, most ferroptosis regulators were identified through synthetic chemical screens or small molecule activators, and it remains unclear whether these canonical pathways explain how iron itself triggers cell death, particularly in vivo. Here, using multi-omics profiling, CRISPR screening, and in vivo models, we uncover a heme-succinate dehydrogenase (SDH)-Coenzyme Q (CoQ) axis that enables CRC cells to buffer iron-induced oxidative stress. Heme-dependent SDH reduces CoQ, which redistributes to mitochondrial and plasma membranes to detoxify lipid ROS as a radical trapping antioxidant. This pathway functions alongside, and in some contexts independently of, canonical ferroptosis regulators. These findings reveal that CRCs co-opt metabolic cofactors not only for growth but also for survival under physiologically toxic iron levels, uncovering new vulnerabilities for therapy.

cancer biology↗

bioRxiv2025

Aspartate transaminases are required for blood development

Red blood cells (RBCs) have a limited lifespan of approximately 120 days. This necessitates continuous RBC production, resulting in [~]200 billion new RBCs made per day to maintain oxygen delivery. Despite this enormous biosynthetic demand, the metabolic pathways supporting erythropoiesis are poorly understood. We profiled metabolites across four independent models of elevated erythropoiesis and a consistent increase in aspartate levels emerged when compared to controls. This suggested a potential role for aspartate metabolism in RBC production. To test this, we deleted the aspartate aminotransferases Got1 or Got2 globally or in an erythroid-specific manner. Loss of either enzyme resulted in anemia, with Got2 deficiency producing a more severe phenotype. Individual loss of either Got or dual Got deletion led to an erythroid defect, where early progenitors accumulated. In human and mouse models of erythropoiesis, GOT1 and GOT2 loss had opposing impacts on aspartate despite exhibiting similar anemic phenotypes, suggesting an aspartate-independent function for these enzymes. GOT1 and GOT2 are also components of the malate-aspartate shuttle (MAS), which regulates NAD(H) homeostasis. However, conditional deletion of another MAS enzyme, Mdh1, did not cause anemia, and alleviating NADH reductive stress in GOT2-deficient cells with cytoplasmic bacterial NADH oxidase (LbNOX) failed to restore erythropoiesis. Instead, transcriptomic and epigenetic analyses revealed dysregulation of chromatin histone modifications in GOT-deficient erythroid cells, implicating epigenetic dysfunction as a driver of defective erythropoiesis. Collectively, these findings identify a previously unrecognized role for GOT1 and GOT2 as a central link between metabolism and epigenetic regulation during erythroid development. These insights may inform the development of new therapeutic strategies for anemia.

biochemistry↗

bioRxiv2025

Purine nucleotides are competitive inhibitors of apo-GOT1

The malate-aspartate shuttle (MAS) plays a key role in cellular metabolism by transferring electrons from cytosolic NADH into the mitochondrial matrix, thereby supporting oxidative phosphorylation, in addition to the citric acid cycle and amino acid metabolism. Here, we sought to identify allosteric regulatory metabolites of the MAS enzymes cytosolic glutamic-oxaloacetic transaminase 1 (GOT1) and mitochondrial GOT2. Using the Atavistik Metabolite Proprietary Screening platform, we identified several structurally similar metabolite hits-- most notably deoxyadenosine monophosphate (dAMP) and deoxyguanosine monophosphate (dGMP)--as candidate interactors with GOT1. Follow-up thermal shift assays revealed that dAMP and dGMP destabilize GOT1 in the absence of its cofactor, pyridoxal 5-phosphate (PLP), but have no destabilizing effect when PLP is present. Crystallographic analysis confirmed that dAMP and dGMP bind in the PLP pocket of GOT1, suggesting competitive binding. Together, these results indicate that nucleotide metabolites can interact with GOT1, offering potential insights into MAS regulation and therapeutic intervention strategies.

molecular biology↗

bioRxiv2025

Targeting HIF-2α in Colorectal Cancer Reveals a Cholesterol Biosynthesis-Dependent Ferroptotic Vulnerability

Colorectal carcinoma (CRC) remains a major cause of cancer-related mortality, with rising incidence in individuals under 55, highlighting the need for novel therapeutic strategies. Hypoxia-inducible factor 2 alpha (HIF-2) has been genetically validated as a critical driver of colorectal tumorigenesis, with intestinal epithelium-specific deletion in mice markedly reducing tumor formation. PT2385, a selective small-molecule HIF-2 inhibitor applied in renal cell carcinoma treatment, has not been evaluated in CRC. Here, we demonstrate that HIF-2 inhibition with PT2385 alone fails to suppress CRC growth in vitro under normoxic or hypoxic conditions and in xenograft models in vivo. To identify vulnerabilities induced by HIF-2 blockade, we performed an unbiased CRISPR metabolic screen. This revealed cholesterol biosynthesis as a critical dependency. Targeting this pathway with clinically approved statins (atorvastatin, pitavastatin, simvastatin) synergized with PT2385 to suppress CRC cell growth, reduce colony formation, and enhance cell death. Mechanistic studies show that combined HIF-2 and HMG-CoA reductase inhibition with statins promotes ferroptosis, characterized by increased lipid peroxidation and depletion of antioxidant metabolites. These effects are fully reversed by the ferroptosis inhibitor liproxstatin-1. Genetic knockdown of HIF-2 or HMG-CoA reductase recapitulated enhanced sensitivity to combination therapy. In vivo, co-administration of PT2385 and atorvastatin significantly reduced tumor growth and increased ferroptotic cell death in xenografts, confirming the mechanistic link. Collectively, these findings uncover a metabolic vulnerability of CRC to dual HIF-2 and cholesterol biosynthesis inhibition, supporting a clinically actionable strategy that leverages safe, FDA-approved statins to potentiate HIF-2-targeted therapy. SignificanceCombined HIF-2 inhibition and cholesterol biosynthesis inhibition using statins reveals a metabolic vulnerability in colorectal cancer that enhances ferroptosis, thus offering a clinically actionable strategy for therapeutic intervention.

cancer biology↗

bioRxiv2025

Glucose Metabolism Sustains Aberrant STAT3 Signaling in Colorectal Cancer via Glycosylated Paracrine Factors.

The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. While STAT3 is canonically activated by cytokines such as IL-6, this activation is typically transient due to negative feedback mechanisms. In CRC, however, STAT3 is aberrantly and persistently activated, promoting tumor cell proliferation and survival. Here, we demonstrate that glucose sustains STAT3 activation independent of cytokine availability. By manipulating glucose metabolism, we show that both glucose and its downstream metabolite, GlcNAc, are essential for maintaining STAT3 activation. Moreover, cells with high basal STAT3 activity produce glucose-dependent glycosylated proteins that can activate STAT3 in neighboring cells via paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that a combination of glycosylated proteins likely acts synergistically. In vivo, inhibition of glycolysis reduces STAT3 activation in tumors, and genetic deletion of STAT3 in subcutaneous tumor models significantly decreases tumor growth. Together, these findings uncover a novel mechanism by which glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.

cancer biology↗

bioRxiv2025

Neuronal SEL1L-HRD1 ERAD regulates one-carbon metabolism and is essential for motor function and survival

Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice (Sel1LSynCre) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age--mirroring core clinical features observed in affected patients--despite preserved neuronal numbers and only modest ER stress. Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulted from induction of the integrated stress response (ISR). Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing new insight into the molecular basis of ERAD-related neurodevelopmental disease. SummaryUsing a neuron-specific Sel1L knockout mouse model, we demonstrate that Sel1L deficiency activates integrated stress responses, rewires one-carbon metabolism, and impairs motor function and survival.

cell biology↗

bioRxiv2025

A lipid metabolism defect is an underlying contributor to Diamond Blackfan anemia syndrome

Analysis of neither Diamond Blackfan anemia syndrome (DBAS) cohorts nor animal models has revealed a potential mechanism for the variable anemia phenotype, a key feature of this disease. Here, we utilized an established Rpl5Skax23-Jus/+ murine DBAS model in order to study this dynamic erythropoiesis deficiency. These haploinsufficient mice exhibit variably penetrant craniofacial and cardiac defects mimicking the phenotypes of DBAS patients bearing RPL5 mutations. We additionally discovered that this specific heterozygous splicing mutation is pathogenic and leads to partial intron retention. By examining the transcriptome of fetal liver erythroid progenitors at E12.5, we demonstrate that the downregulation of erythroid differentiation pathways is consistent with the DBAS phenotype. We also identified dysregulated transcription of lipid metabolism genes with significant reduction in the abundance of Scd1 in a subset of E12.5 mutant embryos at risk for erythroid failure. SCD1, a key enzyme that converts saturated to monounsaturated fatty acids, has not been previously linked to erythropoiesis or DBAS. When anemia was induced in adult mice, pretreatment with an SCD1 inhibitor resulted in improved erythropoiesis. This analysis suggests a key role of lipid metabolism in the variable anemia penetrance in DBAS and highlights a previously unappreciated pathway that may serve as a potential target for drug development. Key PointsO_LIThe variable anemia in Rpl5Skax23-Jus/+mice is triggered by intrinsic/extrinsic stress C_LIO_LIRpl5 haploinsufficient murine and human erythroid progenitors exhibit a lipid metabolism signature with downregulation of Scd1/SCD. C_LI

developmental biology↗

bioRxiv2025

Gut sulfide metabolism modulates behavior and brain bioenergetics

The host-microbiome interface is rich in metabolite exchanges and exquisitely sensitive to diet. Hydrogen sulfide (H2S) is present at high concentrations at this interface, and is a product of both microbial and host metabolism. The mitochondrial enzyme, sulfide quinone oxidoreductase (SQOR), couples H2S detoxification to oxidative phosphorylation; its inherited deficiency presents as Leigh disease. Since an estimated two thirds of systemic H2S metabolism originates in gut, it raises questions as to whether impaired sulfide clearance in this compartment contributes to disease, and whether it can be modulated by dietary sulfur content. In this study, we report that SQOR deficiency confined to murine intestinal epithelial cells, perturbs colon bioenergetics that is reversed by antibiotics, establishing a significant local contribution of microbial H2S to host physiology. We also find that a 2.5-fold higher methionine intake, mimicking the difference between animal and plant proteins, synergized with intestinal SQOR deficiency to adversely impact colon architecture and alter microbiome composition. In serum, increased thiosulfate, a biomarker of H2S oxidation, revealed that intestinal SQOR deficiency combined with high dietary methionine, affects sulfide metabolism globally and perturbs energy metabolism as indicated by higher ketone bodies. The mice exhibited lower exploratory locomotor activity while brain MRI revealed an atypical reduction in ventricular volume, which was associated with lower aquaporin 1 that is important for cerebrospinal fluid secretion. Our study reveals the dynamic interaction between dietary sulfur intake and sulfide metabolism at the host-microbe interface, impacting gut health, and the potential for lower dietary methionine intake to modulate pathology. Significance StatementThe host-microbiome interface is rich in metabolite-based communications that are modulated by diet. Hydrogen sulfide (H2S), which is a respiratory poison at high concentrations, is enriched at this interface, and is detoxified by the host enzyme, sulfide quinone oxidoreductase (SQOR). Given the quantitatively significant contribution of gut to systemic H2S metabolism, we examined how SQOR deficiency restricted to murine intestinal epithelial cells, interacts with high dietary methionine, designed to approximate the difference between plant versus animal protein levels, to affect local and global bioenergetics. Our study revealed profound short- and long-range impacts resulting from the synergy between decreased H2S clearance capacity in gut and high dietary methionine on global energy metabolism, brain pathology, and behavior.

biochemistry↗

bioRxiv2025

Lipidomics profiling identifies β-oxidation as a key process in noise-induced hearing loss

Noise-induced hearing loss (NIHL) is the second leading cause of hearing loss worldwide, and the most common cause in young adults. Despite this burden, the molecular mechanisms by which noise causes damage are poorly understood, and there are no pharmacologic therapies to prevent or reduce noise-induced damage to the inner ear. Here, using targeted and untargeted lipidomics, we show that noise exposure induces changes in fatty acid (FA) and acylcarnitine (CAR) species in the inner ear, a metabolic profile indicative of noise-induced increases in {beta}- oxidation. This conclusion is validated through treatment with Etomoxir, an inhibitor of carnitine palmitoyltransferase 1A, the rate-limiting enzyme of long-chain {beta}-oxidation. Furthermore, we demonstrate that blocking {beta}-oxidation with Etomoxir does not affect hearing in a normal acoustic environment but reduces the extent of hearing loss induced by an intense noise exposure (2 hours, 112 dB SPL, 8-16kHz). Together, our findings provide insights into cochlear energy metabolism and suggest that its modulation could be targeted to reduce NIHL.

neuroscience↗