Central carbon metabolism (CCM) is the primary metabolic hub of the cell, governing energy production and providing precursors essential for a myriad of biosynthetic pathways. Developing analytical tools that can identify and quantify intermediates of these metabolic reactions is crucial for studying cell metabolism in biomedical and biotechnological applications. This study proposes a liquid chromatography (LC)-high-resolution (HR) mass spectrometry (MS) method, covering the CCM of mammalian cell systems. Cells were extracted using a one-step liquid extraction, recovering the hydrophilic metabolites. A stable isotope dilution approach was employed, utilizing a U-13C-yeast internal standard (IS). A LC-HRMS metabolomics method using hydrophilic interaction liquid chromatography (HILIC) coupled to a Zeno-time-of-flight (ZenoTOF) MS was implemented for metabolite semi-quantification. A total of 82 CCM metabolites is reported, of which 77 were confirmed with authentic standards, and for 63 , linearity ranges were obtained. IS normalization enhanced overall robustness, from sample preparation to metabolite semi-quantification. To study the effects on CCM by 5 chemical inhibitors (2-deoxy-D-glucose, etomoxir, UK-5099, rotenone, and 3-nitropropionic acid), our HILIC-HR-TOF-MS method was used. The approach proved efficient in capturing altered metabolite concentrations, within implicated metabolic reactions, as a consequence of inhibitor exposure. Our HILIC-HR-TOF-MS metabolome method is efficient in mapping changes in metabolic intermediates of the CCM in mammalian cells. This approach holds potential for analysing a variety of biological samples across a range of applications, from drug development to biomedicine.
Through integrated transcriptomic and metabolomic analyses, we systematically assessed the role of calcium signaling pathways in adaptation of eelgrass to high-salinity environments. Phenylpropanoid biosynthesis is a crucial metabolic pathway through which calcium signaling involves to salt adaptability of eelgrass. There is a close crosstalk between calcium signaling and nitric oxide in eelgrass. Zostera marina L. (eelgrass), a representative marine submerged angiosperm, exhibits unique traits for salt adaptation. In previous studies, we found that the calcium signaling pathway in eelgrass was activated under high salt conditions, but the specific role of it in adaptation of eelgrass to salt environments is still unclear. In this study, we utilized ethylene glycol tetraacetic acid to inhibit calcium signaling, thereby to find differentially expressed genes and differential accumulated metabolites in eelgrass. Through integrated transcriptomic and metabolomic analyses, we systematically assessed the role of calcium signaling pathways in adaptation of eelgrass to high-salinity environments. Specifically, calcium signaling in roots adjusts homeostasis through cell wall regulation and plant hormone signaling pathways, contributing to osmotic regulation and antioxidant defenses; In stems, calcium signaling primarily mediates ion transport and osmotic regulation; In leaves, the antioxidant defense system would be activated as a compensatory mechanism to alleviate salt stress damage after inhibiting calcium signaling. Notably, phenylpropanoid biosynthesis is a crucial metabolic pathway through which calcium signaling is involved in salt adaptability of eelgrass. Additionally, there is a close crosstalk between calcium signaling and nitric oxide in eelgrass: calcium signaling regulates the expression of nitric oxide synthase, while nitric oxide also influences the expression of several calcium sensor proteins during calcium signaling transduction. These studies provide valuable insights into the role of calcium signaling in eelgrass, contributing to the understanding of the evolutionary processes of marine higher plants, and offering a theoretical foundation for the improved cultivation of salt-tolerant terrestrial crops.
Biofertilizers used in saleable formulations perform poorly in cold Himalayan regions owing to the suppressed metabolic activity of bioinoculants under low temperatures. Cold-adapted Actinobacteria, as potent plant growth-promoting rhizobacteria (PGPR), emerge as viable cold-active bioinoculants for sustainable nutrient management in high-altitude crop cultivation. This perspective aims to document the Actinobacterial metabolic diversity in the glacier bionetwork lying in the North-Eastern and North-Western Himalayan region. A comparative functional bioinformatics study of plant growth-promoting genes demonstrated distinct clustering of Himalayan versus non-Himalayan strains, driven by alanine/aspartate/glutamate metabolism, geraniol degradation, and pyruvate metabolism. This pioneering genomic differentiation of Himalayan actinomycetes from other cold habitats highlights unique cold-tolerance and plant growth-promoting factors that may target particular functionality for crop cultivation in the extreme glacier environment.
Natural killer (NK) cells are promising platforms for off-the-shelf immunotherapy, yet nonviral precision engineering remains limited by poor HDR efficiency, DNA toxicity, and manufacturing challenges. The aim of this study was to establish a high-yield, nonviral knock-in platform. Through extensive in-depth rational screens, we achieved ∼90% HDR insertion of therapeutic payloads while maintaining 100% postediting recovery. By hijacking endogenous transcriptional programs, we installed genetic circuits into defined genomic loci to tune transgene expression. To enable context-dependent therapeutic responses, we integrated a synthetic positive feedback circuit at the CISH locus, which enhanced NK cell persistence and drove strong expression of anti-CD22/19 dual CAR. A hypoxia-responsive IL-12 circuit gated by the PFKFB4 promoter restored cytotoxicity under environmental stress. Finally, we showed this platform is compatible with GMP manufacturing and supports clinical-scale expansion. These findings provide a scalable framework for programmable, nonviral editing of NK cell effector functions for therapeutic and research applications.
Glycated hemoglobin (HbA1c) is a well-established biomarker reflecting chronic glycemic control in diabetes. It accumulates through non-enzymatic glycation of hemoglobin under sustained hyperglycemia and serves as a surrogate of metabolic memory. Emerging in parallel, glycosylated RNA (glycoRNA), small noncoding RNAs bearing covalently attached N-linked glycans, has revealed unexpected roles in immune signaling and glycoimmunomodulation. While glycation and glycosylation represent distinct biochemical processes, both are modulated by glucose availability and cellular stress. This opinion paper aimed to explore the conceptual parallels between HbA1c and glycoRNA, proposing that hyperglycemia-induced metabolic changes may simultaneously influence both processes. In light of these, glycoRNA represents an emerging biomarker as a functional effector in metabolic disease, mirroring the hyperglycemia-driven immunological dimensions of HbA1c with a further advantage of a defined metabolic sequence, which can deepen diagnostics towards disease progression patterns. Though direct experimental evidence is currently limited, we outline plausible mechanistic intersections and suggest methodological frameworks for future research. Therefore, this perspective aims to stimulate interdisciplinary investigation into glycoRNA biology within the broader context of glycemic dysregulation and immune modulation in diabetes.
Biofilms are structured microbial communities that thrive on diverse surfaces in natural, industrial, and host environments. The biofilm lifestyle underpins microbial survival, shapes ecosystem function, and drives persistent infections; yet, for many microbes, the molecular determinants of biofilm development remain poorly defined. Here, we introduce "label-free analysis of biofilms" (LFAB), an imaging method that integrates time-lapse, low-magnification brightfield microscopy with regional optical density measurements to quantify biofilm biomass. Unlike conventional assays, LFAB enables real-time, non-perturbative, and high-throughput monitoring of biofilm dynamics. We validated LFAB across diverse microbial species and observed a strong correlation with traditional biofilm quantification methods. Applying LFAB to Streptococcus pneumoniae, a major human pathogen whose biofilm lifecycle underpins colonization and infection, we uncovered reproducible patterns of microcolony biofilm expansion and growth. LFAB-enabled screening of a transposon mutant library revealed that biofilm formation in S. pneumoniae is shaped by genes spanning carbohydrate metabolism, cell wall synthesis, adhesion, and surface interactions. Further analysis identified choline-binding protein A (CbpA) and its associated two-component regulator, as well as the peptidoglycan hydrolase LytB, as key drivers of microcolony biofilm dynamics. Together, these findings establish LFAB as a broadly applicable platform for dissecting biofilm biology and reveal new regulators of biofilm development in a clinically important pathogen. Biofilms are structured communities of microorganisms that attach to surfaces and persist within a self-produced matrix. The biofilm lifestyle underlies microbial survival in nature, contributes to industrial biofouling, and drives many chronic infections. Despite the importance of biofilms, high-throughput measurements of biofilm growth dynamics are challenging using existing tools, which are often disruptive or are not scalable. To overcome this limitation, we developed "label-free analysis of biofilms" (LFAB), a brightfield-based imaging platform that enables real-time, non-perturbative, and scalable quantification of biofilm biomass. LFAB is broadly applicable across species and correlates strongly with traditional assays. Applying LFAB to Streptococcus pneumoniae, a major human pathogen, we performed a mutagenesis screen, uncovering new genetic regulators of biofilm formation in this organism. These findings advance understanding of S. pneumoniae pathogenesis and establish LFAB as a powerful approach for dissecting the molecular basis of microbial community growth.
Thyroid cancer (TC), the most common endocrine malignancy, presents significant clinical challenges due to the risk of recurrence, metastasis, and treatment resistance, particularly in advanced cases. Driven by lipid peroxidation, ferroptosis is an iron-dependent, regulated cell death pathway increasingly implicated in cancer biology. This review comprehensively summarizes the mechanistic basis of ferroptosis, encompassing iron metabolism, amino acid regulation, lipid peroxidation, and key regulators such as p53, Nrf2, heat shock proteins and its specific implications in thyroid cancer. This study delineates the contribution of both coding and non-coding ferroptosis-related genes as critical modulators of thyroid cancer progression, thereby influencing patient prognosis. The interplay between ferroptosis and the tumor immune microenvironment is also discussed, emphasizing how immune cells like CD8( +)T cells and macrophages influence and respond to ferroptotic signals. Furthermore, we explore the therapeutic potential of targeting ferroptosis using both natural compounds and synthetic agents, which have shown promise in inducing ferroptosis and suppressing tumor growth in preclinical models. Notably, emerging evidence suggests that activating ferroptosis may help overcome radioiodine resistance and improve survival outcomes, particularly in aggressive subtypes such as anaplastic thyroid cancer (ATC). Therefore, the exploitation of ferroptosis offers a promising avenue to address therapeutic resistance and improve prognosis in thyroid cancer, which merits further clinical investigation.
Diabetic foot ulcer (DFU) is a severe complication of diabetes mellitus (DM) characterized by chronic inflammation, impaired wound repair, and systemic metabolic imbalance. This study aimed to identify plasma metabolite signatures associated with DFU and investigate altered metabolic pathways that may serve as potential biomarker. The study aims to identify metabolic alterations and potential biomarkers associated with diabetic foot ulcers, with a focus on the role of vitamin D. We performed an LC/MS/MS-based untargeted metabolomic profiling on plasma sample from DFU patients (n = 22), DM patients without foot ulcers (n = 22), and healthy controls (n = 10). The mean age group was 54years, with comparable gender (male = 9; female = 13) distribution in DFU and DM groups. PLS-DA showed clear metabolic separation between DFU and DM groups. DFU group showed elevated levels of aspartic acid, glutamic acid, taurine, and D-fructose, indicating altered hyperglycemia induced metabolic stress. In contrast, calcitriol and glutathione were significantly reduced (P < 0.01), suggesting compromised antioxidant capacity and immune metabolic regulation. Downregulation of sphingosine-1-phosphate (SIP), L-palmitoylcarnitine, and docosahexaenoic acid (DHA) suggest disruptions in mitochondrial dynamics, and wound healing. Elevated taurine, potentially regulated by the vitamin D receptor (VDR), links vitamin D to tissue homeostasis. This study reveals coordinated disturbances in lipid metabolism, antioxidant defense, and vitamin D signaling in DFU. The identified metabolite signatures highlight pathway-level metabolic alterations associated with impaired wound healing. Our findings suggest that the biological impact of vitamin D in DFU may depend not only on supplementation, but also on its downstream conversion to calcitriol.
The spontaneous transition from α-helix to β-sheet in proteins is a transformative structural event essential for diverse biological functions, yet its dysregulation is a hallmark of protein misfolding diseases. Controlling this transition with molecular precision remains a significant challenge in chemical biology. Here, we report the development of lysine-targeted small hydrophobic chemical constructs (HCCs) designed to bypass native folding pathways and induce α-to-β structural remodeling across a spectrum of model proteins. Through a screening of four HCCs, we identified an activated N,N-dimethyl leucine derivative as a potent, dose-dependent inducer of this conformational switch. Using ion mobility-mass spectrometry and Fourier transform infrared spectroscopy, we demonstrate that these chemical modifications effectively recapitulate the transition from helical architectures to β-sheet-rich assemblies. Beyond structural remodeling, we show that this chemically induced transition drives significant functional shifts, including the precise modulation of cytochrome c catalytic activity and the regulation of amyloidogenic aggregation in lysozyme. Our findings establish HCCs as a versatile platform for interrogating protein conformational landscapes and provide a synthetic strategy to manipulate protein topology. This approach opens new avenues for protein engineering and offers deep insights into the fundamental principles governing protein homeostasis and the molecular basis of proteotoxicity.
Tumor-infiltrating lymphocytes (TILs) are associated with favorable outcomes in high-grade serous ovarian carcinoma (HGSC); however, the tumor microenvironment may modulate immune cell infiltration. This study aimed to evaluate the association between tumor and stromal expression of CXCL12, tumor expression of CXCR4 and CXCR7, immune phenotypes, and survival outcomes in tubo-ovarian HGSC. Eighty-six patients with primary tubo-ovarian HGSC who underwent cytoreductive surgery were retrospectively analyzed. Immunohistochemical expression of CXCL12 (tumor and stroma), CXCR4, and CXCR7 was assessed. TILs were semi-quantitatively scored and dichotomized as low (score 1) or high (scores 2-3). Immune phenotypes were classified as immunogenic, immune-excluded, or immune-ignorant. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods, log-rank tests, and Cox regression. Multivariable logistic regression was used to identify factors associated with high TILs. Median RFS was 23.2 months (95% CI, 19.2-27.1) and median OS was 47.3 months (95% CI, 36.3-55.0). RFS differed significantly across immune phenotypes (log-rank p=0.047), with shorter RFS observed in the immune-excluded phenotype compared with the immunogenic phenotype (hazard ratio, 2.20; 95% CI, 1.14-4.25). High tumor CXCR7 expression was independently associated with a lower likelihood of high TILs (adjusted odds ratio, 0.22; 95% CI, 0.07-0.65). CXCL12 expression was not associated with survival outcomes. Tumor CXCR7 expression is associated with reduced lymphocytic infiltration and an immune-excluded phenotype in HGSC, suggesting a potential role of the CXCR7 axis in shaping the tumor immune microenvironment.
We present BIOMERO 2.0, a major evolution of the BIOMERO framework that transforms OMERO into a FAIR-compliant (findable, accessible, interoperable, and reusable), provenance-aware bioimaging platform. BIOMERO 2.0 integrates data import, preprocessing, analysis, and workflow monitoring through an OMERO.web plugin and containerised components. The importer subsystem facilitates in-place import using containerised preprocessing and metadata enrichment via forms, while the analyser subsystem coordinates and tracks containerised analyses on high-performance computing systems via the BIOMERO Python library. All imports and analyses are recorded with parameters, versions, and results, ensuring real-time provenance accessible through integrated dashboards. This dual approach places OMERO at the heart of the bioimaging analysis process: the importer ensures provenance from image acquisition through preprocessing and import into OMERO, while the analyser records it for downstream processing. These integrated layers enhance OMERO's FAIRification, supporting traceable, reusable workflows for image analysis that bridge the gap between data import, analysis, and sharing.
Sugarcane molasses serves as a vital non-food feedstock for ethanol fermentation, and its efficient utilisation depends on breeding of excellent microbial strains. Therefore, identification of industrial strains for ethanol fermentation is central to improving fermentation efficiency. To identify high-efficiency ethanol-fermenting strains, we developed a method for preparing high-throughput polymerase chain reaction (PCR) templates within 3 min using seven industrial Saccharomyces cerevisiae strains, integrating single-cell morphology and phenotypic variations in ethanol fermentation. Method specificity was confirmed by amplifying and sequencing the internal transcribed spacer region, and the efficiency was validated by extracting genomic DNA using cetyltrimethylammonium bromide (CTAB). Subsequent genetic diversity analysis using random amplified polymorphic DNA (RAPD) with eight effective primers screened from twenty-two random primers revealed genetic similarity coefficients ranging between 0.47 and 0.96. The high-yield strains 1015-04-01 and 1002-03-03 showed the highest similarity (0.96), whereas strain 1015-04-01 and the low-yield strain 1415 exhibited the lowest similarity (0.47). Unweighted pair group method with arithmetic mean (UPGMA) cluster analysis demonstrated that the high-yield strain 1016-02-04, and strains 1415 and 1313 formed a major cluster, and the low-yield strains 1415 and 1313 formed a distinct subcluster; four other high-yield strains constituted a separate cluster, indicating certain genetic differences between high- and low-yield strains, together with partial genetic overlap. The RAPD results exhibited a certain correlation with differences in final ethanol concentration and single-cell morphology, providing preliminary genetic marker references for the rapid identification and screening of high-performance strains used in ethanol fermentation from sugarcane molasses.
The island of Cyprus is located in the Eastern Mediterranean, where leishmaniasis is endemic. Although human visceral and cutaneous leishmaniasis (VL and CL) cases have already been documented on the island, there are limited data on the Leishmania species in northern Cyprus. In this report, we present a CL case diagnosed by both microscopic examination and quantitative real-time PCR (qPCR). The patient, a 79-year-old man residing in northern Cyprus, developed an ulcerative lesion on his left leg. The lesion was surgically excised for histopathological examination, and tissue sections were stained with hematoxylin and eosin (H&E). Microscopic examination of H&E-stained tissue sections revealed Leishmania amastigotes. To confirm the diagnosis and identify Leishmania species at the molecular level, DNA was extracted from the paraffin-embedded tissue sections. Following deparaffinization, qPCR targeting the Leishmania-specific Internal Transcribed Spacer 1 region (located between SSU and 5.8S rRNA genes) was performed. In the qPCR assay, the infecting agent was identified as a member of the L. donovani complex, presumptively L. infantum, based on the melting curve analysis. Our findings provide molecular evidence for the presence of leishmaniasis in northern Cyprus and contribute to addressing the lack of molecular data in the region. Our study also suggests that, due to the zoonotic nature of the identified pathogen, continuous vector and reservoir control programs should be implemented in the region to prevent the spread of the disease.
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Plant-based serine protease inhibitors represent a promising class of bioactive compounds with potential therapeutic relevance. In this study, serine protease inhibitor-enriched peptide fractions were isolated from Zingiber officinale, Allium sativum, and Momordica charantia. Fractions were enriched using ammonium sulfate precipitation, followed by ion-exchange chromatography, and characterized using preliminary physicochemical approaches, including SDS-PAGE (≈ 1-15KDa), UV-visible spectroscopy, Fourier-transform infrared analysis, and amino acid profiling. The peptide-enriched fractions exhibited moderate antibacterial activity against Escherichia coli and Bacillus thurigiensis, with MIC values in the mg/ml range, consistent with partially purified natural fractions. Antifungal activity against Aspergillus niger was observed at approximately 4 mg/mL. In a plant-based Tobacco Mosaic Virus (TMV) model using Nicotiana leaves, the peptide-enriched fractions reduced lesion development, indicating measurable antiviral activity. In this experimental system, the maximum inhibition ranged from approximately 58% to 86% depending on the assay format. Thrombolytic assays demonstrated moderate clot lysis (up to 42.95%) with low hemolytic activity under the tested conditions. Molecular docking suggested potential interactions between peptide motifs and serine protease targets, providing a basis for experimental evaluation. Consistent with this, enzyme inhibition assays demonstrated serine protease inhibitory activity, with IC50 values ranging from 0.15 nM (ASP fraction) to 24 µM (ZOP fraction). Kinetic analyses further revealed distinct modes of inhibition, including competitive, uncompetitive, and mixed mechanisms, depending on the fraction evaluated. As structural identity and purity were not confirmed using the mass spectrometry-based approaches, these findings should be interpreted as an early-stage functional assessment. Definitive structural characterization and further biological validation are necessary to clarify their mechanistic and translational relevance.
Anticancer therapy for patients with gastric cancer on hemodialysis is challenging owing to varying pharmacokinetics and a lack of clinical trial data. This study aimed to evaluate the efficacy and safety of the capecitabine plus oxaliplatin (CapeOX) regimen in a 73-year-old male Japanese patient with stage IV gastric cancer (human epidermal growth factor receptor 2 negative) undergoing hemodialysis. The selected chemotherapy regimen was approximately 50% dose of CapeOX (capecitabine 1500 mg/day on days 1-14 and oxaliplatin 100 mg/day 2-h infusion on day 1) every 3 weeks. Data on plasma drug concentrations, metabolic enzyme genetic polymorphisms, and clinical outcomes were analyzed. Anticancer therapy initially controlled the tumor; however, disease progression and cumulative peripheral neuropathy led to discontinuation after 17 cycles (approximately 12 months of treatment). Oxaliplatin exhibited a rebound increase after each dialysis session (dialyzer clearance [CLdial]: median, 44.12 [interquartile range {IQR}: 24.89 - 70.08] mL/min; hemodialysis removal rate: median, 35.98% [IQR: 19.63 - 54.45]. α-fluoro-β-alanine, the final metabolite of capecitabine, accumulated substantially, although approximately half of them was removed by hemodialysis (CLdial: median, 61.32 [IQR: 24.89 - 70.08] mL/min; hemodialysis removal rate: median, 47.98% [IQR: 44.74 - 50.29]). The UPB1 intronic variant and a DPYD missense mutation (1627 A > G) were detected. The DPYD variant likely influenced 5-fluorouracil metabolism, as its area under the concentration-time curve from 0 to 12 h was comparable to the standard dosage. These findings suggest that appropriate dose reduction and genetic screening might be considered part of chemotherapy guidance to improve safety and effectiveness for patients with advanced gastric cancer undergoing hemodialysis.
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The nuclear receptor NR5A2 (Liver Receptor Homolog-1, LRH-1) has been well characterized in tissues of endodermal origin for the transcriptional control of development, metabolism, and steroidogenesis. In this minireview, we discuss the so far underappreciated expression and role of LRH-1 in hematopoietic cells. We further highlight how deregulation of LRH-1 may contribute to the pathogenesis of leukemia and immune cell-mediated diseases, and how targeting LRH-1 can be employed in immune cell-targeted therapies. Given that LRH-1 expression and function are highly tissue-specific, we further discuss how these contextual differences may be exploited to achieve therapeutic selectivity, especially focusing on the myeloid and T cell lineage. Although current evidence for LRH-1 functions in these immune cells is yet limited, its established role in the transcriptional regulation of development, differentiation, metabolism, proliferation, and cytokine expression of hematopoietic cells suggests a substantial and largely unexploited potential for therapeutic applications in leukemia and immunopathological diseases.
Caterpillars of Lonomia moths (Saturniidae) are among the most medically significant lepidopterans worldwide. Their envenomation causes a severe hemorrhagic syndrome that can be fatal. Although antivenom therapy exists it is only produced using L. obliqua venom extract. More than 60 additional species of Lonomia are distributed across Central and South America, many of which pose an uncharacterized risk to human health. To enable comparative venom studies and genome-guided discovery of toxin genes, we present the first genome assembly of Lonomia casanarensis, a species responsible for most envenomation cases in Colombia. The assembly, generated using PacBio Revio long-read sequencing, spans 483.4 Mb with a scaffold N50 of 7.7 Mb, N90 of 2.4 Mb, and >99% BUSCO completeness. It comprises 154 contigs organized into 118 scaffolds and a complete mitochondrial genome. Phylogenomic analyses based on 1,190 single-copy orthologs place L. casanarensis within a clade of scoli-bearing saturniids. We provide a genomic map of the 21 venom genes previously identified from L. obliqua transcriptomic and proteomic data. This high-quality genome provides a foundation for the development of improved antivenoms and facilitates exploration of novel bioactive compounds from Lonomia venoms.
Prolyl hydroxylase domain enzyme 1 (PHD1) is a key regulator of hypoxic adaptation and metabolic homeostasis, playing an important role in tissue damage and repair. To enable precise pharmacological interrogation of PHD1 function, we developed the first PHD1 degrader using proteolysis-targeting chimera (PROTAC) technology. Our lead compound, SH-26, a cereblon (CRBN)-recruiting PROTAC, induced PHD1 degradation in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner across multiple cell lines. In an acetaminophen (APAP)-induced acute liver injury (ALI) model, SH-26 demonstrated protective effects, attenuating hepatic inflammation and necrosis without detectable cytotoxicity. Mechanistically, SH-26-mediated PHD1 degradation attenuated APAP-triggered reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and NLRP3 inflammasome activation, leading to robust in vivo protection against ALI. Collectively, our work identifies SH-26 as the first effective PHD1 degrader and demonstrates its utility as a chemical tool to dissect the pathological role of PHD1 in ALI.