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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2026

3D ultrasound fascicle tractography for objective muscle architecture analysis.

Muscle architecture shapes muscle function and changes with age, growth, training and disease, yet quantifying three-dimensional (3D) muscle architecture in vivo remains challenging. We introduce a hybrid fascicle tractography approach for freehand 3D ultrasound data that accurately reconstructs 3D muscle fascicles with respect to an objective, anatomically relevant coordinate system defined by the muscle's central aponeurosis. The hybrid approach combines Hessian-based fascicle detection with wavelet-based refinement to generate volumetric fascicle orientations. In a synthetic dataset with known ground truth, fascicle orientations and lengths were estimated with errors of [≤]2{degrees} and ~1.5%, respectively. In vivo, the approach detected physiologically plausible fascicle lengthening in the human tibialis anterior following a passive plantar flexion rotation, whereas diffusion tensor imaging of the same muscle did not. The proposed method enables anatomically relevant, objective and non-invasive quantification of 3D muscle architecture in vivo, providing a practical framework for applications in clinical and applied muscle physiology.

bioengineering↗

bioRxiv2026

PRISM: A Plasmid-based Reporter for Intracellular Spectral Microscopy

Organelles form an interconnected network whose morphology, positioning and interactions reflect cellular state. However, reproducibly quantifying these organelle phenotypes across large cell populations and diverse cell types remains a significant challenge. Here we present PRISM (Plasmid-based Reporter for Intracellular Spectral Microscopy), a PiggyBac-integrable construct encoding five unique fluorescent organelle reporters for spectral microscopy, with an accompanying modular analysis pipeline. PRISM stably labels the Golgi, peroxisomes, endoplasmic reticulum, mitochondria and lysosomes in multiple cell types while remaining compatible with additional molecular or functional probes. The workflow extracts over 500 metrics per cell, describing organelle morphology and distribution alongside pairwise and higher-order contacts. We use PRISM to characterise organelle responses to cytoskeletal perturbation, map PI(4)P redistribution during lysosomal damage, and reveal how Zika virus remodels the organelle landscape during infection. PRISM provides a reproducible approach for investigating organelle network remodelling across biological contexts

cell biology↗

bioRxiv2026

Controlling Molecular Transport through Nanopores by Dynamic Aperture Sizing

Molecular transport through a nanopore determines the information that can be recovered from a translocation signal, yet it remains difficult to control in conventional solid-state nanopores. Rapid translocation reduces the information content and fixed nanopore geometries limit the dimensionality of the signal. Here, we control molecular transport through the development of the pipette-elastomer interfacial nanopore (PEIN), a dynamically reconfigurable solid-state nanopore which addresses these limitations. A PEIN is formed by depressing a glass nanopipette into a soft elastomer, progressively constricting its aperture and enabling continuous control over aperture size, while retaining the simplicity and favourable noise characteristics of glass nanopipette sensing. Using the dynamic aperture size control, DNA velocities could be controlled over more than a twofold range, with dwell times two orders of magnitude greater than observed in glass nanopipettes. DNA-origami rulers further revealed a progressive reduction in polymer velocity during translocation, indicating that hydrodynamic drag alone is insufficient to model forces on the DNA polymer. Finally, by using single- and double-stranded DNA and gold nanoparticles as molecular standards, we demonstrate reversible, size-selective molecular gating with sub-nanometre control. These results establish the PEIN as an accessible platform for controlling molecular transport and probing the relationships among biopolymer conformation, nanoscale confinement and translocation dynamics.

biophysics↗

bioRxiv2026

Repeated listening induces exposure-specific cortical tracking of intelligible continuous speech

Neural encoding of acoustic and linguistic features of continuous speech is sensitive to cognitive factors, such as attention and comprehension. We investigated whether neural tracking is also sensitive to the predictability of speech. Participants were repeatedly exposed to intelligible or unintelligible versions of the same audiobook segment while EEG was recorded. First, we fit encoding models to predict EEG responses from acoustic, sublexical, and lexical features of the presented speech. Model comparisons revealed no reliable improvement in model fit when lexical features were included; subsequent analyses were performed on models including only acoustic and sublexical predictors. Second, we compared prediction accuracy for models trained and tested on the same exposures with models trained and tested across different exposures. While we observed no overall change in prediction performance across exposures, we found that models were exposure-specific: prediction performance was highest within the same exposure and decreased with increasing temporal distance between the training and test exposure. This effect was observed for intelligible but not for unintelligible speech, suggesting that the effect depends on properties unique to intelligible speech, such as the ability to form increasingly specific predictions about upcoming linguistic input, rather than general, non-linguistic factors related to repeated exposure. This distance effect was associated with increased model weights from -90 ms to 130 ms, indicating an enhancement of familiar input during an early cortical processing stage. In summary, these findings indicate that cortical tracking of sublexical speech features is modulated by repeated exposure to intelligible speech, consistent with a role for linguistic predictability.

neuroscience↗

bioRxiv2026

m1A58 acts as a conformational checkpoint coupling human initiator tRNA maturation to translation initiation

tRNAs are characterized by extensive chemical modifications that influence tRNA fate. N1-methyladenosine at position 58 (m1A58) is a widespread core tRNA modification linked to physiological and pathological processes. However, how m1A58 coordinate tRNA folding and processing to ensure translational efficiency in mammalian cells remains largely unknown. Using acute dTAG-mediated degradation and CRISPR-Cas9 knockout, we identified initiator methionine tRNA (tRNAiMet) as selectively vulnerable to m1A58 loss, lacking the isodecoder buffering observed for most other tRNA isoacceptors. NMR analysis of the tRNAiMet showed that m1A58 stabilizes D/T-loop interactions, consistent with a maturation-competent conformation. In vitro processing assays further demonstrated that m1A58 promotes RNase P-mediated 5'-leader removal and RNase Z-mediated 3'-trailer cleavage, while La/SSB protects accumulated precursors. Disrupting this checkpoint impaired the assembly of the eIF2-containing 43S pre-initiation complex and global protein synthesis, which was substantially rescued by adding m1A58-modified tRNAiMet. Acute TRMT6 degradation elicited temporally coordinated gene-expression responses involving proteostasis, transport and signaling. Together, these findings establish m1A58 as a conformational checkpoint coupling human initiator-tRNA maturation to translation initiation and stress responses.

molecular biology↗

bioRxiv2026

Structure-Constrained Intrinsic Timescales Across Tasks

Intrinsic neural timescale (INT) quantifies the persistence of spontaneous neural dynamics and offers a principled metric for characterizing brain-wide temporal organization. Although a hierarchy of INTs has been established during rest, how task engagement reconfigures this organization and how it is constrained by the structural connectome (SC) remain poorly understood. Here, we systematically mapped whole-brain INT using high-resolution fMRI data from the Human Connectome Project during rest and seven tasks spanning working memory, gambling, motor, language, social, relational, and emotion domains. Task engagement induced robust, regionally heterogeneous changes in INT while largely preserving the brain-wide temporal hierarchy across cognitive states. SC-INT coupling remained strong but consistently decreased during tasks, indicating that anatomical architecture continues to constrain INT, although its influence is attenuated under task demands. To investigate these findings mechanistically, we employed a multiscale, whole-brain neuronal-network model, which revealed that INT increase and peak within a broad critical-like regime. Strong SC-INT coupling, as observed empirically, emerged in the subcritical regime, weakened progressively with increasing network excitability, and reversed in the supercritical regime. These results demonstrate that task engagement reconfigures INTs while maintaining their hierarchical organization, suggesting that both resting and task states operate largely within a common subcritical dynamical regime.

neuroscience↗

bioRxiv2026

Spatiotemporal expression of the zebrafish pax9 gene that is essential for median fin patterning

PAX9 is an evolutionarily conserved paired-box transcription factor that is critical for embryonic development and human diseases. The mouse model has been predominantly used to investigate Pax9 functions. Zebrafish has emerged as a complementary vertebrate model for various human diseases, including cancers. Until recently, the functions of the zebrafish pax9 gene in jaw and hematopoiesis have started to be uncovered. However, detailed pax9 spatiotemporal expression, molecular mechanisms, and potential functions in other zebrafish organs remain largely unknown. With the technical advances in CRISPR-Cas9, non-homologous end joining (NHEJ) has made knockin and knockout a convenient way to examine endogenous gene expression in vivo and to generate a loss-of-function allele simultaneously. Here, we first generated pax9 knockin fish lines by inserting fluorescent proteins at the start of the endogenous pax9 coding region. Then, we examined pax9 expression in real time from early embryonic stages through adulthood. Except for previously reported expression domains, we were able to identify pax9 expression in high resolution in the paired and median fins, where pax9 marks anterior fin rays. Moreover, our knockin and knockout mutants showed increased fin ray number in median fins, but no evident effect on paired fins in pax9 null mutants. Thus, PAX9 is critical for median fin patterning in zebrafish.

developmental biology↗

bioRxiv2026

Early establishment acts as a selective filter shaping climate-associated genomic variation in European beech

Climate change is increasing drought and heat stress in European forests, raising concerns about the capacity of long-lived tree species to respond to rapidly changing environmental conditions. While local adaptation has been documented in many forest trees, it remains unclear whether newly established seedlings, which form the forests of the future, are able to persist and adapt to these new climatic conditions. Here, we investigated genomic differences between naturally regenerated seedlings and trees of European beech (Fagus sylvatica) across the three regions of the German Biodiversity Exploratories using low-coverage whole-genome sequencing (5x) of 1,032 individuals. Population structure was primarily driven by geographic region, whereas genetic diversity was similar across life stages. Despite this genome-wide similarity, we detected allele frequency shifts between trees and seedlings, concentrated in narrow genomic windows. These shifts were strongest in surviving seedlings, suggesting that environmental filtering during early establishment may contribute to shaping the genetic composition of regenerating populations. The strongest signals were observed within the Swabian Alb, where sampled seedlings were 2-years old and had experienced a longer period of potential filtering prior to sampling. Genotype - environment association analyses identified loci associated with climatic variables, and subsequent GO enrichment analyses of genes linked to these loci revealed significantly more enriched GO terms in seedlings than in trees, suggesting stronger environmental filtering by the current climate in seedlings. In particular, we found associations with maximum air temperature, relative humidity, soil moisture, and precipitation, affecting genes involved in stress responses, growth, metabolism, and developmental processes. Together, our results demonstrate that young cohorts of European beech differ genetically from trees and reveal genomic patterns consistent with life-stage-dependent environmental filtering. These findings suggest that the genetic composition of early life-stages is already altered by current environmental conditions, possibly contributing to adaptation to new climatic conditions.

ecology↗

bioRxiv2026

Hidden molecular states of bacterial replicons beyond the chromosome-plasmid dichotomy

Bacterial genomes are organized into autonomous replicons, traditionally classified as either chromosomes or plasmids-a binary framework that underpins genome annotation and evolution models. Yet whether this binary framework captures the full diversity of replicon organization remains unclear. Here we show that bacterial replicons occupy three recurrent organizational states rather than two canonical categories. By integrating quantitative measures of chromosome-plasmid sequence affinity (plasmidness) across more than 72,000 replicons from 21 bacterial genera, we identify a distinct class-intermediate replicons-that occupies a positional and functional middle ground. These replicons are plasmid-sized, harbor substantial chromosomal sequence ancestry, and lack canonical replication signatures typically associated with either class. Multiple complementary molecular properties converge on this same state. Comparative genomic analyses reveal their enrichment near recurrent chromosome remodeling regions and reveal close evolutionary ties to conjugative and antimicrobial resistance plasmids. Metagenomic data further corroborate their presence across natural ecosystems. Together, these findings reveal a previously unrecognized replicon state and redefine bacterial genome organization beyond the chromosome-plasmid dichotomy.

microbiology↗

bioRxiv2026

Mycoplasmal endosymbionts of Trichomonas vaginalis are associated with reduced risk for Chlamydia trachomatis endometrial infection in asymptomatic, coinfected, women.

Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis, the most common curable non-viral sexually transmitted infection, and Chlamydia trachomatis is a bacterial pathogen that can ascend to the upper genital tract and cause pelvic inflammatory disease, infertility, and ectopic pregnancy. T. vaginalis harbors bacterial endosymbionts, including Candidatus Malacoplasma girerdii, an obligate symbiont, and Metamycoplasma hominis, which can live freely or symbiotically. In a 16S rRNA sequencing study of the cervicovaginal microbiome of women at high risk for chlamydial infection, Ca. M. girerdii abundance was one of 13 features predicting lack of chlamydial spread to the endometrium, despite no direct association between T. vaginalis infection and reduced chlamydial ascension. Investigating the relationship between these microorganisms further, we found that T. vaginalis vaginal abundance correlated positively with chlamydial burden in women whose infection was confined to the cervix, while a nonsignificant inverse relationship was seen in women with endometrial spread. Among participants with high chlamydial burden, Ca. M. girerdii was detected exclusively in women without endometrial infection. Both endosymbionts trended toward more frequent detection, and higher abundance, in coinfected women without endometrial spread, while M. hominis abundance correlated strongly with T. vaginalis burden in this group. These findings suggest that mycoplasmal endosymbionts of T. vaginalis, rather than T. vaginalis itself, are microbial factors limiting chlamydial ascension, and point to a three-way interaction between parasite, endosymbiont, and bacterial pathogen that shapes upper genital tract C. trachomatis infection risk.

microbiology↗

bioRxiv2026

A family-wide atlas of human connexin docking compatibility

Gap junction (GJ) channels mediate direct intercellular communication by allowing the exchange of ions, metabolites, and signaling molecules between neighboring cells. Humans express 21 connexin (Cx) isoforms that can assemble into homotypic or heterotypic channels, creating a large potential interaction landscape that shapes tissue-specific communication networks. However, the rules governing which connexin isoforms can compatibly dock remain incompletely defined. Extracellular loop 2 (EL2) sequence features have been implicated in docking specificity and used to classify connexins into two canonical compatibility groups, K-N and H, but these assignments remain largely predictive. Most potential heterotypic connexin pairings have never been experimentally tested. This incomplete interaction map limits our ability to predict which connexin combinations can assemble, how isoform co-expression shapes intercellular communication, and how these relationships are altered or exploited in disease and engineered systems. Here, we used the FETCH (Flow Enabled Tracking of Connexosomes in HEK Cells) assay to evaluate docking compatibility across the complete human connexin family. To support family-wide compatibility mapping, we used literature-supported heterotypic interactions to define a data-driven FETCH score threshold for high-confidence interaction compatibility. Homotypic FETCH measurements varied substantially across the 21 connexin isoforms, with 15 producing mean scores above the empirical threshold. We then extended FETCH analysis to all 210 pairwise heterotypic isoform combinations. The resulting interaction landscape largely recapitulated expected motif-class relationships, including enrichment within the two canonical compatibility groups, but also identified neighboring-group interactions and unexpected cross-group pairings that represented clear exceptions to class-based predictions. Consistent with these findings, pairwise EL2 motif similarity was only modestly associated with threshold-based interaction classification, indicating that EL2 similarity alone was insufficient to predict compatibility outcomes. Together, these findings suggest that motif class provides a broad organizing framework for connexin compatibility, but that pairwise docking specificity also depends on yet-unresolved isoform-specific determinants that produce neighboring-group relationships and clear cross-group exceptions. Notably, Cx46, a lens Cx also associated with melanoma and breast cancers, emerged as a broadly permissive isoform capable of interacting with partners from both major compatibility groups and more than half of the connexin family. Together, these findings establish the first family-wide experimental atlas of human connexin docking compatibility, defining canonical interactions, previously unrecognized pairings, and exceptions to established compatibility rules. This atlas provides a foundation for defining the molecular determinants of connexin specificity, understanding how isoform diversity shapes intercellular communication, and designing gap junction channels with controlled docking behavior.

biochemistry↗

bioRxiv2026

A CO2-limitation-induced cytosolic repressor enables shutdown of the algal CO2-concentrating mechanism

Aquatic photosynthetic organisms face limited CO2 availability because CO2 diffuses slowly in water and most dissolved inorganic carbon (Ci) exists as HCO3- at physiological pH. To overcome this limitation, aquatic photoautotrophs operate CO2-concentrating mechanisms (CCMs) that elevate CO2 around Rubisco and sustain carbon fixation. Because CCM operation consumes energy, it must be suppressed when CO2 becomes abundant, but how this shutdown occurs remains poorly understood. In Chlamydomonas reinhardtii, the nuclear protein CBP1 was identified as a CCM repressor, but its loss causes only partial derepression under high CO2, indicating that an additional mechanism is required for complete shutdown. Here, we identify High-Affinity CCM Repressor 1 (HCR1), a cytosolic protein related to CBP1, as a second repressor. Under high CO2, hcr1 mutants retained high affinity for Ci and derepressed CCM and photoacclimation genes. Combined disruption of HCR1 and CBP1 further increased Ci affinity, approaching that of wild-type cells with a fully induced CCM under CO2 limitation, and promoted the accumulation of Ci transporters. HCR1 loss also prevented redistribution of the chloroplast regulator CAS away from the pyrenoid and was accompanied by retention of a pyrenoid starch sheath. In contrast, LCIB, a chloroplast CO2-recapture protein, relocated normally. Unexpectedly, HCR1 accumulated during CO2 limitation and declined after transfer to high CO2. These results show that CCM shutdown is an active transition rather than the passive reversal of induction. We propose that CBP1 restrains CCM1-dependent transcription, while HCR1 is preloaded during CO2 limitation to terminate the CAS-associated, starch-sheathed, high-affinity state when CO2 becomes replete.

plant biology↗

bioRxiv2026

Assessing specificity testing in Lesion Network Mapping

Lesion Network Mapping (LNM) is a framework used for identifying symptom-related brain circuits by projecting lesion locations onto a normative connectome. Recent methodological investigations have raised concerns about the biological interpretation and specificity of the circuits derived using this method, with published LNM maps often showing high similarity across clinically unrelated conditions. Specificity testing has subsequently been put forward as the decisive step to ensure specificity to the symptom in question, accompanied by the argument that this step was not evaluated in the original methodological investigation. Yet, sensitivity testing, specificity testing, case-control LNM, permutation of group labels, and symptom-based LNM involve related operations on connectivity matrix C. We expand on specificity testing in LNM, clarify its relationship to other LNM steps and variants, and examine the persistent repetition among LNM specificity networks across studies. These considerations advance our understanding of the disease-specificity limitation of LNM and encourage the development of new methodological approaches for identifying brain circuits underlying psychiatric and neurological disorders.

neuroscience↗

bioRxiv2026

Quantifying sprint force-velocity elasticity: implications for individualized training decisions

This study aimed to (1) develop an elasticity framework for the sprint force-velocity (F-V) relationship and (2) examine how maximal force (F_{0}), maximal velocity (v_{0}), and sprint distance modulate the four derived elasticity metrics, and (3) explore these elasticity metrics' interrelation. After modelling the F-V relationship differential equation, four elasticity metrics were defined as force elasticity (F_{e}), the elasticity of sprint time to F_{0}; velocity elasticity (v_{e}), the elasticity of sprint time to v_{0}; the force-velocity elasticity norm {(\mathrm{F}-\mathrm{V}}_{\mathrm{EN}}=\sqrt{F_{e}^{2}+v_{e}^{2}}), capturing the combined sprint time sensitivity to proportional changes in F_{0} and v_{0}; and the force-velocity elasticity ratio {(\mathrm{F}-\mathrm{V}}_{\mathrm{ER}}=F_{e}{\div v}_{e}), indicating which variable dominates the sprint time response. Model simulations showed that F_{e} decreased with rising F_{0} and increased with rising v_{0}, while v_{e} showed the opposite pattern. With increasing sprint distance, F_{e} decreased and v_{e} increased. Given its negligible effect on sprint time, ignoring air resistance yields a conservation law (2F_{e}+v_{e}\equiv 1), indicating that a gain in one elasticity metric necessarily diminishes the other in a fixed proportion. This framework also identifies a valley distance (d_{valley}) at {\mathrm{F}-\mathrm{V}}_{\mathrm{ER}}=2, where {\mathrm{F}-\mathrm{V}}_{\mathrm{EN}} is minimized (\sqrt{0.2}) and sprint time is least responsive to changes in F-V relationship variables. Empirical data confirmed that the two theoretical laws still hold approximately when air resistance is considered. By linking changes in F_{0} and v_{0} to sprint time across different distances, the elasticity framework provides a quantitative basis for estimating the theoretical sprint time response to documented changes in F-V relationship variables.

biophysics↗

bioRxiv2026

Mechanistic modeling of bacterial translation initiation across growth conditions

Translation frequency in bacteria depends on how ribosomes, mRNAs, and initiation factors are allocated across growth conditions. Here, we developed a mechanistic ODE-based model of Escherichia coli translation that represents initiation, elongation, termination, and coupled auxiliary processes. Growth-dependent abundances were derived from physiological relationships and reprocessed omics data, and simulated outputs were compared with translation-frequency and active-ribosome references. The model predicts a continuous shift from complex-formation-limited toward ribosome-limited behavior as growth increases. This shift is characterized by a decline in free-ribosome abundance, whereas initiation-factor pools remain largely unbound and do not become depleted in parallel. Together with the implemented IF-dependent kinetic term, this preserved availability provides a model-internal route through which productive initiation can be maintained despite increasing ribosome utilization. Consistently, transcript-wide ribosome loading remains below its theoretical maximum, while COG-level simulations reveal distinct sector-specific translation-frequency trajectories. The study therefore provides a resource-allocation framework for interpreting how mRNA--ribosome interactions shape bacterial translation across growth conditions.

systems biology↗

bioRxiv2026

Ancient Somatosensory Circuit Architectures Employ Flexible Molecular Strategies

The extent to which conserved neural circuit architectures depend on shared molecular specification programs remains unclear. Here, we address this question by examining the somatosensory system of the little skate, Leucoraja erinacea, an early-diverging vertebrate that retains ancestral features of both finned and limb-based body plans. We show that core features of somatosensory circuit organization, including laminar organization of the spinal cord and dorsally restricted targeting of sensory afferents, are deeply conserved. Unexpectedly, the molecular programs specifying dorsal root ganglion (DRG) sensory subtypes diverge extensively from those of mammals. Although DRG neuron subtype specification and spinal connectivity rely on target-derived cues, skates employ distinct neurotrophin receptor and transcription factor identity codes. These findings support a model in which conserved spinal circuit architectures provide a stable scaffold that leverages flexible sensory neuron specification programs, enabling the evolutionary diversification of vertebrate somatosensory systems. HighlightsO_LIIntegrated analysis of spinal cord and DRG neuronal diversity in Leucoraja erinacea C_LIO_LILaminar organization of the dorsal spinal cord is an ancestral vertebrate feature C_LIO_LIDivergent neurotrophin receptor and transcription factor codes in sensory neurons C_LIO_LIConserved target-dependent regulation of sensory identity and connectivity C_LI

neuroscience↗

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗

bioRxiv2026

Cryo-EM structures reveal the mechanism of phosphatidylserine remodeling by membrane-bound glycerophospholipid O-acyltransferase 1

Lands cycle remodeling of glycerophospholipid acyl chains is crucial for cells to maintain appropriate membrane composition. Glycerophospholipids are cleaved at the glycerol sn2-position by phospholipase A. The lysophospholipids are reacylated by enzymes of the membrane-bound O-acyltransferase (MBOAT) family to incorporate specific fatty-acyl chains to adjust membrane properties. How MBOAT enzymes recognize specific acyl-CoA donors, select lysophospholipid acceptors, and release products is unclear. Phosphatidylserine (PS), a critical anionic phospholipid, controls membrane surface charge, signaling-protein recruitment, and cell-death-associated membrane recognition, and PS acyl-chain remodeling is linked to ferroptosis resistance. Here, we showed that MBOAT1 preferentially generates monounsaturated fatty acid-containing PS from lyso-PS. High-resolution cryo-electron microscopy structures of human MBOAT1 captured distinct binding poses of the fatty acyl donor, lyso-PS acceptor, and PS product. With lipidomics, enzymology and molecular dynamics simulations, these structures reveal the mechanism and pathway of MBOAT1-dependent PS remodeling.

biochemistry↗