Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 163 records · Page 9Linked to original sources

bioRxiv2026

Autoregressive forecasting of future single-cell state transitions

Predicting future cell state transitions from static transcriptomic snapshots is vital for understanding and steering cellular dynamics. Although existing trajectory and RNA velocity methods can infer local transitions within observed data, they are fundamentally limited in extrapolating long-range cellular dynamics. Here, we introduce CellTempo, an autoregressive generative framework that enables long-range forecasting of cell state trajectories directly from static transcriptomic snapshots. CellTempo is pretrained on scBaseTraj, a large-scale collection of multi-step cellular transition sequences constructed by integrating diverse experimental technologies and data sources. Across diverse biological systems, CellTempo accurately predicts long-range lineage progression and reconstructs unseen cellular potential landscapes. It further distinguishes transient perturbation responses from long-term cell-fate changes, enabling prioritization of candidate compounds for cell-fate engineering. These results demonstrate that long-range cellular dynamics are inferable from static observations, establishing a foundation for predictive and controllable modeling of cell fate.

bioinformatics↗

bioRxiv2026

A time-calibrated phylogeny of hummingbirds supports stepwise diversification in the Andes

Hummingbirds (Trochilidae) represent the second largest avian family, with [~]356 species occupying diverse habitats across the Neotropical and Nearctic regions. Their extensive diversification includes notable adaptations to extreme environments, with nearly one-third of extant taxa belonging to the predominantly high-altitude Coquettes and Brilliants. Although recent work proposed a monophyletic Andean clade uniting these groups, consistent with rapid radiation during Andean orogeny, we find no support for this relationship. Using 2,949 nuclear loci sampled from 47 species spanning all nine major hummingbird clades, we recover a different evolutionary pattern: a stepwise sequence of diversification in which Brilliants are sister to a broader assemblage comprising Coquettes, the genus Patagona, Emeralds, Mountain Gems, and the recently diverged Bees. By assembling complete mitochondrial genomes, we additionally detect significant discordance between nuclear topologies and those derived from the mitogenome and Z chromosome. Analyses of gene-tree heterogeneity show that incomplete lineage sorting is pervasive across the phylogeny, with particularly strong impacts on branches associated with Andean diversification. Divergence-time estimation further indicates that the major Andean radiation--including Brilliants, Coquettes, Emeralds, Bees, and Mountain Gems--originated around [~]14 Ma, with the three younger clades diversifying [~]12 Ma, coinciding with both the mid-Miocene Andean uplift and the mid-Miocene Climate Transition that increased habitat heterogeneity and likely promoted rapid speciation. To support future phylogenomic efforts, we identify a reduced set of highly informative, independent protein-coding loci and present a near-complete species-level phylogeny constrained by our autosomal backbone. Our findings highlight the importance of integrating loci with distinct inheritance modes to detect and interpret phylogenetic incongruence in rapid radiations.

evolutionary biology↗

bioRxiv2026

A Multi-Organ Single-Cell Atlas Maps Allergen and Organ-Specific Cellular Dynamics in the Progression from Food Allergy to Anaphylactic Shock

The transition from food allergic sensitization to life-threatening anaphylactic shock (AS) with complex multi-organ cellular interactions has been poorly understood. We herein conducted a multi-organ single-cell sequencing of heart, lung, and intestinal tissues from mouse models of food allergy, sensitized to bovine serum albumin (BSA) or ovalbumin (OVA), across both sensitization (Phase I) and anaphylactic shock (Phase II). We found that organ-specific pathologies included cardiac vascular dysfunction with pericyte loss and cardiomyocyte adaptation, distinct lung responses (Th2/B-cell predominance with BSA vs. neutrophilia with OVA), and profound intestinal remodeling featuring Paneth cell expansion. We also identified conserved inflammatory pathways (e.g., NOD-like receptor, NF-{kappa}B, JAK-STAT signaling) and unique organ specific signatures. Notably, phase-dependent reprogramming showed NLRP3 inflammasome activation and suppressed anti-inflammatory responses during AS. Cell-cell communication networks shifted from stromal-immune crosstalk in Phase I to dominant myeloid-vascular/neuroimmune interactions in Phase II. We further linked early extracellular matrix remodeling to late-stage neuromodulatory responses in Schwann and smooth muscle cells. This multi-organ atlas elucidates the coordinated, organ-selective immune cascade driving FA to AS progression, providing a foundational resource for developing targeted therapeutic strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/703914v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@19ffd9forg.highwire.dtl.DTLVardef@c3fda3org.highwire.dtl.DTLVardef@141174corg.highwire.dtl.DTLVardef@60ac5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Unravelling genome-wide mosaic microsatellite mutations at single-cell resolution

Short tandem repeats (STRs), or microsatellites, are highly mutable genomic elements that modulate gene regulations and are implicated in a range of human diseases. However, detecting mosaic STR mutations at single-cell resolution remains challenging due to both technical and biological complexities. To address this, we developed BayesMonSTR, a robust algorithm that enables accurate detection of mosaic STR mutations. Using this tool in single-cell analysis of human tissues, we reveal an accumulation of longer mosaic STR insertions and deletions (indels) in aging mitotic and post-mitotic cells. Strikingly, prefrontal cortex (PFC) neurons accumulate a higher burden of STR mutations than B cells or lung epithelium, with aged neurons exhibiting a particularly pronounced increase in longer STR deletions. These mutations are enriched at transcription start sites (TSSs) and active enhancers of highly expressed genes. Our work establishes a foundation for genome-wide, hypothesis-free discovery of disease-associated mosaic STR mutations and reveals a previously unexplored landscape of mosaic STR variation in development and aging.

bioinformatics↗

bioRxiv2026

The genetic repertoire of the deep sea: from sequence to structure and function

The deep sea as the largest and maybe most hostile environment on Earth is still underexplored especially regarding its genetic repertoire. Yet, previous work has revealed significant habitat-specific deep-sea biodiversity. Here, we present an integrated deep-sea genetic dataset comprising 502 million nonredundant genes from 2,138 samples and 2.4 million predicted structures, and used it to link specific protein structures with genetic variants associated with life in the deep sea and to assess their biotechnology potential. Combining global sequence analysis with biophysical and biochemical measurements revealed unprecedented sequence diversity, yet substantial structural conservation of proteins. Especially proteins involved in replication, recombination, and repair were identified to be under rapid evolution and with specialized properties. Among these, a structurally divergent helicase exhibited advantages in controlling nanopore sequencing speed. Thus, our work positions the deep sea as a unique evolutionary engine that generates and hosts genetic diversity and bridges genetic knowledge with biotechnology.

bioinformatics↗

bioRxiv2026

Bacterial exo-α-sialidases subvert the complement system through desialylation

The complement system is a central pillar of innate immunity, yet how bacterial glycan-modifying enzymes subvert complement function remains poorly understood. Bacterial sialidases remove terminal sialic acids from host sialoglycans, but their direct impact on complement immunity is unclear. Here, we investigate the impact of six sialidases from five human pathogens on complement immunity using an integrated approach combining genetics, biochemistry, glycobiology, mass spectrometry, and structural biology. We demonstrate that major complement components (IgG, C1q, C4, and C5) and regulators (Factor I, Factor H, and C4bp) are sialylated, and that bacterial sialidase-mediated desialylation suppresses complement activation and surface deposition, thereby enabling complement evasion. Despite extensive sequence diversity, biochemical and structural analyses reveal that all examined sialidases share a conserved six-bladed {beta}-propeller catalytic domain and cleave both N-acetylneuraminic and N-glycolylneuraminic acids, the predominant mammalian sialic acids. Together, these findings uncover a conserved mechanism by which diverse bacterial pathogens disable complement immunity through desialylation.

microbiology↗

bioRxiv2026

SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis

The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 leads to GSSG accumulation in the ER and a liposome-based assay demonstrates that SLC33A1 directly transports GSSG. Cryo-EM structures and molecular dynamics simulations reveal how SLC33A1 binds GSSG and identify residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induces ER stress and dependency on the ER-associated degradation (ERAD) pathway, driven by a shift in protein disulfide isomerases (PDIs) toward their oxidized forms. Altogether, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.

cell biology↗

bioRxiv2026

Asymmetric architecture and adaptation of Treponema flagella

Spirochetes exhibit a distinctive corkscrew-like motility driven by periplasmic flagella that wrap around the cell body in a supercoiled configuration, yet the structural basis of this unique propulsion remains poorly understood. Here we combine cryo-electron microscopy, cryo-electron tomography, and genetic and biochemical analyses to determine the assembly and adaptation principles of the supercoiled flagellar filament in Treponema denticola, a major periodontal pathogen. Near-atomic structures reveal a glycosylated FlaB flagellin core encased by a previously unrecognized asymmetric sheath. The major sheath protein FlaA forms the bulk of the sheath and mechanically couples to the core through defined interfaces required for efficient motility, whereas four minor sheath proteins (FlaA1, FlaA2, FlaAP1, and FlaAP2) assemble along the concave side of the filament to accommodate intrinsic curvature. Disruption of this asymmetric core-sheath organization compromises force transmission and impairs motility, establishing coordinated asymmetric assembly as a fundamental mechanism underlying spirochetal motility.

molecular biology↗

bioRxiv2026

How different AI models understand cells differently

AI single-cell foundation models (scFMs) are believed to be able to learn essential relations in cell transcriptomics with the attention modules in Transformer, but there is no method to reveal what they actually learned. We observed that different models may grasp different aspects of relations. To unravel the mystery, we propose scGeneLens, a framework for dissecting how scFMs perceive cells. We employed a sparse block attention to replace the original attention mechanism to concentrate attentions into a few dominant gene-gene relations, used attention propagation to trace how the relations propagate across Transformer layers, and used integrated gradients to disentangle the relative contributions of gene identity and expression in cell representations. We applied it to scFoundation and scGPT and show that they exhibit pluralistic perceptions of cells: scFoundation emphasizes relations among cell-type marker genes, resulting in stronger cell-type separability, whereas scGPT focuses more on genes involved in shared cellular pathways and core biological activities, leading to representations that generalize across conditions. The framework provides a unified lens for probing what scFMs learn about cells and offers actionable insights for the design of future cellular foundation models. Our code can be seen in https://anonymous.4open.science/r/scGeneLens-B771/.

bioinformatics↗

bioRxiv2026

Pan-genome and multi-omics analyses reveal the genomic basis of symbiotic evolution in the mycoheterotrophic medicinal orchid Gastrodia elata

Mycoheterotrophy represents an extreme evolutionary strategy in which plants abandon photosynthesis and become obligately dependent on fungal partners for carbon and nutrients. Gastrodia elata, a medicinal orchid forming long-term symbioses with Armillaria and Mycena, provides a compelling system to investigate the genomic basis of obligate plant-fungus mutualism. Here, we generate a chromosome-level genome assembly (1.09 Gb) of a dark-red G. elata accession and construct a pan-genome from 12 Gastrodia accessions to dissect the evolutionary consequences of mycoheterotrophy. Phylogenomic analyses reveal pervasive hybridization across cultivated germplasm and demonstrate that tuber morphology more accurately reflects intraspecific relationships than stem color, challenging the traditional color-based taxonomy. Comparative genomic analyses reveal a pronounced degeneration of photosynthetic capacity. We detect no intact nuclear-encoded rbcS loci, which would preclude assembly of the Rubisco holoenzyme and thus canonical Calvin-Benson carbon fixation. Notably, a subset of photosynthesis-related genes is retained and transcriptionally active, suggesting their co-option into non-photosynthetic regulatory roles. Despite millions of years of intimate association with fungal partners, we detect no evidence of fungal-derived horizontal gene transfer based on a multi-step phylogenomic validation pipeline, indicating that G. elata-fungus mutualism is sustained through metabolic exchange rather than genetic integration. We further identify the Gastrodia antifungal protein (GAFP) gene family as a key molecular innovation underlying symbiotic homeostasis. The recently derived Class 1 GAFP lineage exhibits distinct domain architecture, tandem expansion, and elevated expression, consistent with enhanced regulation of fungal overgrowth. Finally, we delineate a specialized nutrient-acquisition framework adapted to obligate heterotrophy, in which fungal trehalose hydrolysis supplies hexose carbon via an expanded sugar transporter protein (STP) repertoire, while organic nitrogen is assimilated through amino acid and oligopeptide transporters coupled with urease-mediated conversion, compensating for the loss of nitrate uptake and reduction pathways. Together, these results establish a pan-genomic blueprint for symbiotic adaptation and reductive genome evolution in G. elata.

genomics↗

bioRxiv2026

Immunopeptidomics reveals peptide antigens preferentially presented in psoriasis lesional skin of HLA-C*06:02 carriers

BackgroundHuman leukocyte antigen (HLA)-C*06:02 is a major genetic risk factor for psoriasis and understanding the HLA-C*06:02-presented peptide antigen repertoire (immunopeptidome) in the skin of patients is crucial for identifying autoantigens. Yet, no skin immunopeptidome data from patients stratified by their HLA-C*06:02 status exists. ObjectiveWe analysed biopsies from lesional and non-lesional skin of patients with psoriasis vulgaris (n=12), guttate psoriasis (n=8), or from skin of healthy controls (n=16). MethodsHLA class I and class II peptide complexes were isolated by serial immunoprecipitation and HLA-bound peptides identified by liquid chromatography-tandem mass spectrometry. HLA-C*06:02 genotyping was performed by polymerase chain reaction. ResultsOver 99,000 non-redundant peptide ligands were identified across all samples. Substantially more HLA class I and class II peptides were detected in lesional psoriatic skin compared to matched non-lesional and healthy skin. Three peptides predicted to bind HLA-C*06:02, including MRASSFLIV from the known psoriasis marker peptidase inhibitor 3 (PI3), were identified in all lesions of HLA-C*06:02-positive patients but were rarely detected or absent in HLA-C*06:02-negative patient lesional skin and not detected at all in unaffected skin. Keratinocyte differentiation-associated protein (KRTDAP) was a notable source of lesion-specific HLA class II ligands contributing three out of six peptides detected in more than half of the lesional samples. ConclusionActive psoriatic lesions display an altered and expanded immunopeptidome compared to unaffected skin. We have identified numerous unreported, lesion-specific HLA-bound peptides and their source proteins. These findings offer insights into the pathobiology of psoriasis and provide a resource for future functional studies. CAPSULE SUMMARYA selection of immunopeptides is presented exclusively in lesional skin of HLA-C*06:02+ patients with psoriasis that may represent antigenic drivers of disease.

immunology↗

bioRxiv2026

Genomic diversity, antibiotic resistance, and maturation-dependent adhesion of F18 enterotoxigenic Escherichia coli strains in porcine intestinal cells

Enterotoxigenic Escherichia coli (ETEC) strains expressing F4 and F18 fimbriae are major causes of neonatal and post-weaning diarrhea in swine. Although epithelial maturation influences susceptibility in vivo, its impact on ETEC-host interactions remains poorly defined. This study characterizes emerging F18 ETEC isolates using a differentiated porcine intestinal cell model. Three F18 strains (3EC1, 27EC1, 3247EC), a porcine F4 strain, and human ETEC H10407 were analyzed by comparative genomics for virulence factors, toxin genes, and antimicrobial resistance determinants. Adhesion assays were performed using IPEC-1, IPEC-J2, and Caco-2 cells conditioned to Early (6 days post-confluence, DPC), Mid (9 DPC), and Late (16 DPC) maturation states. Transcription of F18-binding receptors (FUT1, FUT2) was quantified by RT-qPCR. IPEC-1 cells exhibited significantly higher FUT1 and FUT2 expression than IPEC-J2, corresponding to approximately two-fold stronger adhesion by most F18 isolates. Strain 3EC1 showed a distinct adhesion peak at 9 DPC, approaching F4 levels, while F4 and H10407 consistently displayed the highest adhesion across all models. Genomic analyses revealed substantial heterogeneity among F18 strains in fimbrial loci, flagellin, lipopolysaccharide biosynthesis, and antimicrobial resistance. Strain 3EC1 uniquely carried stx2e, and non-classical EAST1 variants were detected in 3EC1 and 3247EC. All F18 isolates encoded hlyE and were {beta}-hemolytic; 3247EC harbored 28 antimicrobial resistance genes. The IPEC-1/IPEC-J2 maturation stages recapitulate age-dependent susceptibility to ETEC, likely driven by FUT1/2 expression levels. The combination of strong adhesion, stx2e, and extensive antimicrobial resistance in F18 strains underscores their evolving virulence and supports this model as a refined platform for studying porcine ETEC pathogenesis. ImportanceETEC remains a leading cause of neonatal and post-weaning diarrhea in swine, yet the biological basis for age-dependent susceptibility is not fully understood. This study demonstrates that maturation of porcine intestinal epithelial cells strongly influences F18 ETEC adhesion, driven in part by developmental regulation of the F18-binding receptors FUT1 and FUT2. By integrating comparative genomics with a physiologically relevant in vitro maturation model, we reveal substantial diversity in virulence and resistance among F18 strains, including strong adhesion capacity, stx2e, and extensive antimicrobial resistance in strain 3EC1. These findings highlight the evolution of ETEC toward increased persistence and pathogenic potential in swine populations. The interaction between the maturation-dependent IPEC-1 and IPEC-J2 cell lines and ETEC offers a valuable tool for evaluating intervention strategies to reduce weaning piglet susceptibility to ETEC infection.

microbiology↗

bioRxiv2026

A conserved and predictable pluripotency window in callus unlocks efficient transformation in grasses and beyond

A major bottleneck in plant biotechnology is the inefficient and genotype-dependent regeneration of callus, which severely limits genetic transformation and functional studies across many species. This barrier is acutely exemplified in the study of beneficial plant-microbe interactions, such as the Epichloe-grass symbiosis--a system conferring remarkable stress tolerance to its host but hindered by a lack of efficient genetic tools. To address this, we established a chromosome-scale genome for an Epichloe native host grass Achnatherum inebrians. We discovered that the expression dynamics of evolutionarily conserved cell pluripotency regulators (CPRs) including ARF5/7/19, BBM, WUS/WOX5 and CUC1/2 serve as a precise molecular predictor for callus regenerative capacity, revealing that pluripotency is dynamic and peaks within a narrow, definable time window. Harnessing this predictable window enabled the development of a highly efficient transformation system for A. inebrians (49.4% efficiency). Crucially, this CPR-based strategy proved generalizable: applied to wheat and the legume sainfoin, it pinpointed species-specific optimal regeneration windows, boosting shoot regeneration rates to 65.7% and 87.5%, respectively. Collectively, our work provides an integrated research system and a rational design principle that removes a key barrier to uncovering molecular mechanisms in plant systems, particularly the Epichloe-enhanced stress tolerance symbiosis.

plant biology↗

bioRxiv2026

TCRAD: An End-to-End Framework for Antigen-Targeted T Cell Receptor Design

Understanding and engineering T-cell receptor (TCR) specificity is central to personalized immunotherapy and antigen discovery. However, while antigen-conditioned TCR design approaches have begun to emerge, most frameworks still focus on scoring candidate TCR-pMHC pairs, and achieving high hit rates in designing functional, target-reactive TCRs remains a key bottleneck. Here, we present TCRAD, a deep learning pipeline that performs de novo design of TCR CDR3{beta} sequences conditioned on antigenic peptides. TCRAD comprises three modules: Sequence Generation, Sequence Filtration, and Structure Prediction. TCRAD can effectively generate antigen-specific CDR3{beta} sequences, discriminate functional binders with high accuracy, and predict bound and unbound structures with performance comparable to or exceeding state-of-art methods. Experimental validation using the 1G4/NY-ESO-1 system demonstrated that the model can design novel functional TCRs capable of surface expression, specific pMHC binding, and that 17.2% candidates (5 of 29) elicit antigen-induced activation. Together, these results establish TCRAD as a powerful framework for TCR sequence design, offering a scalable path toward rational engineering of antigen-specific TCRs for cancer immunotherapy, vaccine development, and personalized immunotherapeutics.

bioinformatics↗

bioRxiv2026

Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A

Targeted therapies eliminate cancer cells by inhibiting oncogenic signaling; however, tumor cells often evade cytotoxicity through proteomic and epigenetic reprogramming that enables survival. These adaptive responses may create collateral cellular stresses, such as DNA damage, that can be therapeutically exploited. When unresolved, DNA damage leads to chromosomal instability (CIN), a potential source of vulnerability. Whether KRAS inhibition induces DNA damage or CIN in KRAS-mutant non-small cell lung cancer (NSCLC) has not been established. Here, we show that the KRASG12C inhibitor LY3499446 induces CIN in KRAS-mutant NSCLC cell lines. A targeted compound screen revealed that the extent of CIN induction by KRASG12C inhibition strongly correlates with therapeutic synergy with the selective Aurora kinase A inhibitor LSN3321213. Mechanistically, KRASG12C inhibition stabilizes cyclin B1 during mitosis through activation of mitotic ATR/ATM signaling. In the presence of Aurora Kinase A inhibition, cyclin B1 stabilization delays mitotic exit and diverts cell fate from mitotic slippage or division toward mitotic catastrophe. Together, our findings identify CIN as a predictive marker of response to combined KRASG12C and Aurora Kinase A inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies.

cancer biology↗

bioRxiv2026

Histology-Aware Graph for Modeling Intercellular Communication in Spatial Transcriptomics

Cell-cell communication (CCC) is essential to how life forms and functions. Recent tools achieve single-cell-resolved CCC inference utilizing spatial transcriptomics (ST). However, most ignore the modeling of tissue contexts surrounding cells, causing high false-positive/negative rates. Here, we propose HARMONIC, a CCC inference method integrating multimodal ST and hematoxylin and eosin (H&E)-stained images. HARMONIC causally modeling the transcriptomic-to-contextual relationships for CCC inference. The state-of-the-art performance was verified across ST platforms, species and healthy/diseased status, on both synthetic and biological samples. HARMONIC was applied in various real-world scenarios, especially on tissues with clear morphological boundaries, including cortical layers in mouse brain, medullary-cortex structures in mouse kidney, as well as tumor-stromal/immune interface. Significant refinement of false-positive/negative predictions was observed compared to ST-only CCC tools.

bioinformatics↗

bioRxiv2026

Mechanistically Defined Epoxide- and Aziridine-2-carboxamide Electrophiles Enable Stereoselective Covalent RNA Modulation

RNA remains a largely untapped target for covalent small-molecule intervention due to the lack of electrophiles with predictable reactivity and stability in biological settings. Here, a mechanistically defined and tunable class of epoxide- and aziridine-2-carboxamide electrophiles that enable structure-guided covalent targeting of RNA is described. These warheads arise from an unexpected hydrolytic rearrangement of 3-chloropivalamide precursors under physiological conditions and selectively react with guanine N7, with reactivity and stability controlled by substitution pattern, linkage chemistry, and stereochemistry. Application to two distinct RNA targets demonstrates generality: epoxide- and aziridine-based ligands covalently modify pathogenic r(CUG)exp repeat RNA and disrupt RNA-protein interactions in vitro and in cells, while structure-guided placement on a flavin scaffold yields stereoselective covalent modulators of the flavin mononucleotide (FMN) riboswitch with validated reaction site and cellular activity. Together, this work establishes epoxide- and aziridine-2-carboxamides as a versatile platform for covalent RNA targeting and provides a general framework for the rational design of stereochemically controlled RNA-reactive small molecules.

biochemistry↗

bioRxiv2026

Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction

Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.

cell biology↗