Metabolic dysfunction–associated steatotic liver disease (MASLD) is a globally prevalent disease, yet its genetic architecture remains incompletely characterized. We integrated genome-wide association study data from multiple cohorts totaling nearly 3 million individuals of European ancestry and applied cross-trait genomic modeling of hepatic fat and seven cardiometabolic traits to construct an MASLD-specific polygenic architecture. We identified 128 risk variants across 100 loci and prioritized 55 effector genes, including established (e.g., PNPLA3 and TM6SF2) and previously unreported candidates (e.g., NRXN3 and FRMD5). A phenome-wide scan of the MASLD polygenic risk score revealed broad associations spanning hepatic, cardiometabolic, renal, endocrine, and neuropsychiatric systems. Using a two-step, proteome-wide Mendelian randomization across >4900 plasma proteins, we identified potential mediators linking MASLD to disease. Validation in population-based cohort pinpointed seven proteins (e.g., FURIN, aldehyde dehydrogenase 2, and apolipoprotein M) mediating up to 50.6% of the cardiometabolic risk attributable to MASLD. Our findings delineate the polygenic architecture of MASLD, highlight its multisystem consequences, and nominate translational biomarkers for precision prevention.

Cotton (Gossypium hirsutum L.) is a globally important cash crop. Cytoplasmic male sterility (CMS) is a key biological tool for hybrid seed production. However, a systematic, stage-specific proteomic profile of CMS anther development in cotton remains lacking. To address this, we employed, for the first time in cotton CMS research, a high-resolution quantitative proteomic approach using data-independent acquisition mass spectrometry (DIA-MS) to compare the CMS line C2P5A and its maintainer line C2P5B across three critical anther developmental stages: pollen mother cell (Pms), tetrad stage (Tds), and mononuclear stage (Ms). A total of 498 significantly differentially expressed proteins (DEPs) were identified, with 194 upregulated and 304 downregulated. Bioinformatic analysis revealed that these DEPs are significantly enriched in key metabolic pathways essential for anther development, including glycolysis/gluconeogenesis, pyruvate metabolism, the tricarboxylic acid (TCA) cycle, starch and sucrose metabolism, and fatty acid degradation. Notably, we identified 12 aldehyde dehydrogenases (ALDHs) and several cytochrome P450 proteins associated with reactive oxygen species (ROS) homeostasis and pollen wall formation. This study presents a systematic, stage-resolved proteomic atlas of CMS in cotton using DIA-MS, which reveals that widespread dysregulation of central energy and secondary metabolite pathways underpins the sterility phenotype. Our integrated multi-omics and functional validation approach provides novel molecular insights into CMS mechanisms and pinpoints potential targets for hybrid breeding.

Acute myocardial infarction caused by thrombosis is a major cause of mortality. A polymorphism in aldehyde dehydrogenase 2 (Aldh2) rs671 is found in approximately 30% to 50% of East Asians, and it is a risk factor for acute myocardial infarction. This mutation impairs ALDH2 function, but the effect of ALDH2 on platelet activation and thrombosis is unknown. Platelets were isolated from platelet-specific Aldh2-/- mice and ALDH2E506K knockin mice (which correspond to the human Aldh2 rs671 gene mutation) as well as from healthy human donors with Aldh2 rs671. Arterial thrombosis was measured in a ferric chloride (FeCl3)-induced thrombosis mouse model. The efficacy of Alda-1, an ALDH2 activator, in mitigating thrombogenesis was measured in ALDH2E506K mice. Using a murine model of myocardial infarction, we analyzed the effects of platelet Aldh2 on microthrombosis and infarct expansion post myocardial infarction. In addition, we enrolled 118 patients of different Aldh2 rs671 genotypes (GG, GA, and AA) diagnosed with ST-segment-elevation myocardial infarction to analyze the association between rs671 genotype and platelet activation and thrombosis. Platelets from Aldh2-/- and ALDH2E506K mice showed enhanced agonist-induced aggregation, ATP release, integrin αIIbβ3 activation, P-selectin release, spreading, and clot retraction. Human platelets with the Aldh2 rs671 variant also exhibited increased activation. Mutation of Aldh2 or platelet-specific knockout of Aldh2 exacerbated thrombus formation in a mouse model of thrombosis. The ALDH2 activator Alda-1 reduced thrombosis in ALDH2E506K mice. We explored pathways mediating the effect of Aldh2 on platelet activation. We found that platelets lacking Aldh2 produced more reactive oxygen species and less nitric oxide than wild-type (WT) platelets. Furthermore, platelets lacking Aldh2 were also more susceptible to activation by aldehydes. Additionally, platelets from mice lacking Aldh2 had increased elevated mitophagy and hyperactivity. ACAD10 mediated some of the effects of ALDH2 on mitophagy. Mice lacking Aldh2 had increased microthrombosis and myocardial infarct expansion. Finally, elevated platelet activation and thrombus markers were also observed in plasma from patients with ST-segment-elevation myocardial infarction who had the rs671 variant. The Aldh2 rs671 variant, which impairs ALDH2 function, increases platelet activation and thrombus formation in vivo through aldehyde accumulation and reactive oxygen species buildup. Abnormal ACAD10 homeostasis might also contribute to this hyperactivity by enhancing platelet mitophagy. Our findings suggest potential of ALDH2 as a novel antiplatelet target. Future studies are needed to explore the effects of more aggressive antiplatelet therapy for patients at risk of myocardial infarction who carry the Aldh2 rs671 mutation.

While androgen receptor (AR) pathway inhibitors such as enzalutamide have demonstrated significant therapeutic efficacy in prostate cancer (PCa) treatment, the inevitable development of acquired resistance continues to pose a major clinical challenge in managing advanced PCa. We characterized Neurexophilin 4 (NXPH4) as a contributor to enzalutamide resistance (EnzR). Gain- and loss-of-function studies were conducted in PCa cell lines and mouse subcutaneous xenograft models to elucidate the role of NXPH4 in castration-resistant prostate cancer (CRPC). Additionally, the regulatory mechanisms of gene expression were assessed using a series of molecular and biochemical experiments. Our study demonstrates that AR as a transcriptional activator of NXPH4. Elevated NXPH4 expression facilitated PCa proliferation under enzalutamide treatment through mitochondrial metabolic reprogramming. We identified that NXPH4 partially localizes to mitochondria and physically interacts with aldehyde dehydrogenase 1 family member L2 (ALDH1L2), a critical enzyme in one-carbon metabolism. Androgen deprivation stimulated NXPH4 mitochondrial translocation and enhanced its binding to ALDH1L2. NXPH4-mediated metabolic reprogramming promotes PCa progression. Notably, the combination of NXPH4 knockdown and enzalutamide treatment showed potent synergistic effects, significantly suppressing cell proliferation in vitro and substantially inhibiting tumor growth in vivo. These findings reveal a previously unrecognized mechanism of EnzR and identify the NXPH4-ALDH1L2 complex as a promising therapeutic target for CRPC treatment.

Aldehyde dehydrogenase family 6A1 restores implant osseointegration in hyperlipidemia by disrupting ROS-ERS-LPO vicious cycle and reestablishing adhesion-osteogenesis coupling.

A new horizon for the anesthetic drug dyclonine.

Weizmannia coagulans BC99 Alleviates Alcohol-Induced Oxidative Stress and Gut Barrier Dysfunction via Modulation of Butyrate Metabolism: A Randomized, Double-Blind, Placebo-Controlled Trial.

Engineering of ethylene glycol (EG)-trophic Escherichia coli enables fast growth on EG for closed-loop PET biodegradation.

DPEP1 mediates regulation of mitochondrial quality control via FOXO1/ALDH1L2 axis to attenuate ferroptosis in pulmonary endothelial cells to alleviate sepsis-associated acute lung injury.

Integrated multi-omics demonstrates DNA demethylation-driven activation of the RgMYB2-RgG10H4 axis enhancing iridoid glycoside biosynthesis in Rehmannia glutinosa.

Alcohol-induced liver injury remains a major global health concern, while effective strategies that facilitate alcohol metabolism are still limited. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase 2 (ALDH2) play central roles in hepatic ethanol metabolism, their catalytic reactions are stoichiometrically coupled to nicotinamide adenine dinucleotide (NADH) production. However, many existing NADH probes suffer from short excitation/emission wavelengths, high background interference, and limited dynamic ranges, restricting their application in enzyme-related screening. Herein, we report a near-infrared fluorescent probe, BOD-NH (Ex/Em = 715/760 nm), featuring low background fluorescence, high photostability, and a broad linear response toward NADH (0-200 μM). Leveraging these properties, an enzyme-coupled screening strategy was established to evaluate NADH generation associated with ADH- and ALDH2-catalyzed reactions. Screening of a natural product library identified Citri Grandis Exocarpium as an extract exhibiting pronounced activity in both enzyme systems. Subsequent spectrum-effect correlation analysis combined with HPLC-Q-TOF-MS/MS characterization identified naringin as a key bioactive constituent. Enzyme-based assays showed that naringin was associated with enhanced ADH- and ALDH2-related NADH generation. In vivo studies further demonstrated that naringin administration was associated with accelerated ethanol and acetaldehyde clearance, improved behavioral recovery following acute alcohol exposure, and attenuation of alcohol-induced liver injury accompanied by reduced oxidative stress and inflammation. Collectively, this work establishes BOD-NH as a practical NADH-responsive analytical tool for enzyme-coupled screening applications and identifies naringin as a bioactive natural product with potential value for further investigation in alcohol metabolism-related modulation.

Amide bond formation is widely used in pharmaceutical synthesis, typically involving stoichiometric coupling reagents to activate carboxylic acid substrates for a condensation reaction. As an alternative approach, we repurposed aldehyde dehydrogenases into oxidative amidases by creating a more hydrophobic and spacious catalytic pocket for amines to capture the thioester intermediate. This biocatalyst efficiently facilitates the formation of amide bonds between diverse aldehydes and amines. We also developed a two-step enzymatic cascade to synthesize amides from broadly available aliphatic alcohols. This biocatalytic strategy enabled the redesign of synthetic routes for five drug molecules. Our findings highlight the potential of oxidative amidases in advancing the synthesis of structurally diverse drug molecules through efficient amide bond formation.

Disulfiram (DSF) is a well-established inhibitor of aldehyde dehydrogenases (ALDHs) and an FDA-approved drug for chronic alcoholism. DSF has gained attention as a versatile scaffold for drug repurposing. Its metabolite, diethyldithiocarbamate (DDTC), mediates multiple biological effects via metal chelation and covalent modification of key cysteine residues. Beyond its established anticancer properties, DSF modulates cancer stem cells, reactive oxygen species, proteasome function, and drug-resistance pathways. It also shows promise in metabolic disorders, including type 2 diabetes and obesity, by targeting enzymes such as fructose-1,6-bisphosphatase and α-glucosidase, and influences energy expenditure and autophagy. DSF exhibits antimicrobial and antiparasitic activity, enhances antibiotic efficacy against multidrug-resistant bacteria, and demonstrates antischistosomal and anti-Trichomonas effects, while also providing radioprotective benefits. The clinical translation of DSF is limited by poor solubility, rapid metabolism, and off-target effects; consequently, the development of DSF analogs has become a major focus. Structural optimization has yielded derivatives with improved selectivity, stability, solubility, and target specificity, enabling precise modulation of key enzymes while reducing adverse effects. A key structure-based strategy involves introducing bulkier substituents to exploit differences in ALDH active-site architecture and achieve target selectivity. This concept is exemplified by compounds (1) and (2), in which bulky substituents confer selective inhibition of ALDH1A1 while sparing ALDH2. This review provides a comprehensive overview of DSF analogs, their molecular mechanisms, and therapeutic potential, highlighting their promise as multifunctional agents for cancer, metabolic disorders, infectious diseases, and radioprotection.

Low-dose 650 nm red light has been found to slow myopia progression, although the underlying mechanisms remain unclear. This study aimed to investigate its antioxidative effects and molecular pathways. An oxidative stress model was established in ARPE-19 cells by treatment with hydrogen peroxide (H₂O₂) at concentrations of 0, 0.5, and 0.75 mM. The cells were then irradiated with red light for 9 minutes, twice daily for 2 days, with an equivalent-power white light group serving as a control. Following irradiation, oxidative stress was quantified using a DCFH-DA assay, and DNA damage was assessed by γ-H2AX immunofluorescence. For the in vivo study, mice received ocular irradiation with red light (9 minutes/session, twice daily for 5 days) using a white light-exposed group as a control. Changes in axial length were measured post irradiation using anterior segment optical coherence tomography. Subsequently, retinal pigment epithelial (RPE) cells were isolated from the mice for RNA sequencing to analyze differential mRNA expression. Quantitative real-time PCR (qPCR) and Western blotting were employed to validate the expression of specific genes associated with ocular diseases. At a concentration of 0.75 mM hydrogen peroxide, red light irradiation significantly reduces oxidative stress levels compared to the control group. RNA sequencing data revealed that there were 274 genes upregulated and 225 genes downregulated in RPE cells from mouse eyes illuminated with the 650 nm red light. The gene encoding aldehyde dehydrogenase 3A1 (ALDH3A1), which is significantly upregulated after red light irradiation, plays an important role in protecting ocular structures from oxidative damage. qPCR and Western blot analyses confirmed that ALDH3A1 was heightened in RPE cells from mouse eyes in vivo and in cultured human RPE cells in vitro illuminated by the 650 nm red light. ALDH3A1 may play a part in myopia improvement upon 650 nm red light illumination.

Slugs are significant agricultural pests and act as vectors for zoonotic parasites. However, current molluscicide options are limited and associated with substantial environmental risks. This study investigates the role of aldehyde dehydrogenase (ALDH) in the biosynthesis of farnesoic acid (FA), a key intermediate in the sesquiterpenoid hormone pathway, in two slug species: Philomycus bilineatus and Laevicaulis alte. Transcriptomic analysis revealed that both species possess conserved sesquiterpenoid biosynthetic pathways, yet they exhibit distinct levels of ALDH gene expression and differences in FA content. RNA interference (RNAi)-mediated gene silencing was employed to validate the potential of these candidate genes as targets for molluscicide development. Structural modeling of ALDH proteins using AlphaFold2 demonstrated notable divergence in the architecture of their active sites, suggesting species-specific enzymatic properties. Citral, a known inhibitor of ALDH, significantly reduced FA production in vivo and exhibited contact toxicity against both slug species. The lethal concentration 50 (LC50) values were determined to be 378.2 g/L for P. bilineatus and 85.2 g/L for L. alte, respectively. Molecular docking analyses indicated that citral binds within the conserved substrate-binding tunnel of ALDH, potentially inhibiting the oxidation of farnesal. These findings establish ALDH as a critical enzymatic target for disrupting endogenous hormone biosynthesis in slugs and support the development of novel, eco-friendly molluscicides targeting the sesquiterpenoid pathway.

The aryl hydrocarbon receptor (AHR) is a transcription factor prominently expressed at barrier sites, while aldehyde dehydrogenase 3 family member A1 (ALDH3A1) is a metabolic enzyme implicated in oxidative stress. However, their roles in ferroptosis remain poorly understood. Imperatorin (IMP) is a bioactive compound derived from traditional Chinese medicine. Here, we demonstrate that IMP is a natural agonist of AHR, inhibiting LPS-induced ferroptosis, inflammation, and barrier damage in lung epithelial cells by promoting AHR nuclear translocation and activation. Mechanistically, IMP-activated AHR stimulated the Nrf2/HO-1/GPX4 axis and enhanced ALDH3A1 expression, thereby inhibiting ferroptosis-related Fe2+ accumulation, ROS production, and lipid peroxidation. The in vivo results showed that oral IMP activated the AHR/ALDH3A1 and Nrf2/HO-1/GPX4 pathways in lung tissue, thus improving lung dysfunction and inflammation in acute lung injury (ALI) mice induced by LPS. Notably, ALDH3A1 is a key downstream signaling protein of AHR. An AHR inhibitor reversed the IMP-induced upregulation of ALDH3A1, whereas an ALDH3A1 inhibitor blocked the anti-ferroptotic Nrf2/HO-1/GPX4 pathway and diminished the lung-protective effects of IMP-activated AHR both in vitro and in vivo. These findings indicate that the AHR/ALDH3A1 axis may represent a previously unrecognized therapeutic target for ferroptosis and provide insight into IMP as a therapeutic strategy to prevent and treat ALI.

ABSTRACTEthylene glycol (EG) is a hazardous alcohol present in various household and industrial products. After being metabolized by ethanol dehydrogenase and aldehyde dehydrogenase, it can produce glycolate, acetaldehyde, and oxalate, leading to acute kidney injury. Renal failure is mainly caused by tubular damage induced by metabolites such as glyoxylate and oxalate, and may also be related to tubular obstruction caused by oxalate crystal precipitation. A 35‐year‐old Chinese man was brought to the emergency department in an unconscious state with a suspected history of EG ingestion. Laboratory examination revealed significant metabolic acidosis with elevated anion gap, acute kidney injury, and hyperkalemia, suggestive of possible EG poisoning. Renal biopsy revealed acute tubular necrosis, with numerous oxalate crystals forming in the tubules of the patient, confirming the diagnosis of EG poisoning with oxalate nephropathy. Treatment included fluid resuscitation, bicarbonate therapy, ethyl alcohol administration, and hemodialysis. After early and active treatment, the patient's consciousness recovered, acidosis improved significantly, and no further dialysis treatment was required.

This study measured the concentrations of blood ethanol (EtOH) and acetaldehyde (AcH) in mice to examine the roles of aldehyde dehydrogenase 2 (ALDH2) and sex following intragastric administration of EtOH. The experiment utilized males and females of two mouse strains: C57BL/6N (wild-type, WT) and Aldh2-knockout (Aldh2-KO) mice. Aldh2-KO mice lack the ALDH2 enzyme, leading to the accumulation of high levels of AcH in the blood. The mice were fasted for approximately six hours before EtOH administration. EtOH (1.0, 2.0, and 3.0 g/kg) was administered intragastrically, and blood samples were collected at 30, 60, 120, 180, 240, and 300 minutes post-EtOH administration through retro-orbital puncture. The samples were then analyzed using headspace gas chromatography. The results for both male and female WT mice showed that EtOH and AcH levels increased in a dose-dependent manner, peaked at 60 min post-ingestion, and then gradually decreased. While there were no significant differences in blood EtOH concentrations between males and females, the concentrations of AcH were significantly higher in female mice than in male mice, indicating potential sex-related differences in EtOH metabolism. In Aldh2-KO mice, the EtOH and AcH levels increased initially and peaked at 30-60 minutes post-ingestion, with no significant differences in EtOH or AcH concentrations between the sexes. While the concentrations of EtOH in both male and female Aldh2-KO mice gradually decreased, the concentration of AcH remained elevated until six hours post-ingestion due to the ALDH2 deficiency inhibiting AcH oxidation. Our findings emphasize the importance of considering the influences of sex and ALDH2 when researching the effects of alcohol, particularly in relation to the EtOH byproduct AcH.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for estrogen receptor-positive (ER+) breast cancer, yet resistance remains a major clinical challenge. Although CDK4/6i induce G1 arrest and therapy-induced senescence (TIS), the exact nature of this senescent state and its contribution to resistance are not well understood. To explore this, we developed palbociclib- (2PR, 9PR, TPR) and abemaciclib- (2AR, 9AR, TAR) resistant ER+ breast cancer sublines through prolonged drug exposure over six months. Resistant cells demonstrated distinct phenotypic alterations, including cellular senescence, reduced mitochondrial membrane potential, and impaired glycolytic activity. Cytokine profiling and enzyme-linked immunosorbent assay (ELISA) validation revealed a non-canonical senescence-associated secretory phenotype (SASP) characterized by elevated growth/differentiation factor 15 (GDF-15) and serpin E1 (plasminogen activator inhibitor-1, PAI-1) and absence of classical pro-inflammatory interleukins, including IL-1α and IL-6. IL-8 levels were significantly elevated, but no association with epithelial-mesenchymal transition (EMT) was observed. Resistant cells preserved their epithelial morphology, showed no upregulation of EMT markers, and lacked aldehyde dehydrogenase 1-positive (ALDH1+) stem-like populations. Additionally, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) was strongly upregulated in palbociclib-resistant cells. Together, these findings identify a distinct, non-canonical senescence phenotype associated with CDK4/6i resistance and may provide a foundation for identifying new vulnerabilities in resistant ER+ breast cancers through targeting SASP-related signaling.

Torularhodin is the monocyclic C40 carotenoid with the β-ring and a terminal carboxyl group at the acyclic part, with long conjugated double bonds, only synthesized in fungi called red (oleaginous) yeasts, e.g., the genera Rhodotorula and Sporobolomyces. This unique red pigment with strong antioxidant properties is promising for use in food additives, nutritional supplements, and cosmetics. We aimed to produce torularhodin in Escherichia coli through the identification of the biosynthesis genes needed for its heterologous production, while no genes oxidizing torulene to torularhodin had been reported. The Rhodotorula toruloides crtI (CAR1) and crtYB (CAR2) genes, which were chemically synthesized, proved to lead to the complete conversion of phytoene into torulene when they were introduced into an E. coli cell that carried the Pantoea ananatis crtE and Haematococcus pluvialis IDI genes. We found that the Planococcus maritimus genes coding for C30 carotenoid terminal oxidase (crtP/crtNb/cruO) and aldehyde dehydrogenase (aldH/crtNc), through their introduction into the E. coli transformant synthesizing torulene, mediated the efficient oxidations of torulene to torularhodin, and resulted in the production of torularhodin as the dominant carotenoid. This is the first report of torularhodin production in a heterologous host. We also identified the aldH/crtNc gene in R. toruloides.