Impulse oscillometry in the diagnosis of cough variant asthma in children.

BACKGROUND: Cough variant asthma (CVA) is one of the most common causes of chronic cough in children worldwide. The diagnosis of CVA in children remains challenging. This study aimed to assess the diagnostic utility of impulse oscillometry (IOS) pulmonary function in children with CVA. METHODS: This study included children aged 4 to 12 years diagnosed with CVA who underwent IOS pulmonary function and bronchodilation (BD) tests. A control group of healthy children was matched. Pre- and post-BD IOS parameters were recorded and presented as mean ± standard deviation or median. Receiver operating characteristic (ROC) curves were plotted, and the area under the curve (AUC) was calculated to evaluate the discriminatory potential of the IOS parameters for diagnosing CVA. RESULTS: A total of 180 patients with CVA and 65 control subjects were included. The baseline IOS parameters in the CVA group, except X5%pred, were significantly greater compared to the control group. After inhalation of salbutamol sulfate, all IOS parameters improved significantly in the CVA group. However, Z5%pred, R5%pred, and R20%pred remained greater in the CVA group compared to the control group. The improvement rates of IOS parameters in the CVA group significantly surpassed those in the control group. The ROC curve results for pre-BD IOS parameters and the improvement rate during the BD test showed that the combinations of pre-Z5%pred+△Z5% and pre-R5%pred+△R5% achieved the highest AUC value of 0.920 and 0.898, respectively. The AUC values of these combined parameters surpassed those of individual ones. CONCLUSIONS: This study highlights that children with CVA exhibit greater IOS parameters compared to healthy children. The changes in IOS parameters during the BD test provided valuable diagnostic information for CVA, and the combination of various parameters can help pediatricians accurately identify CVA in children.

A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

Advances in MET tyrosine kinase inhibitors in gastric cancer.

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.

ANRIL: A Long Noncoding RNA in Age-related Diseases.

The intensification of the aging population is often accompanied by an increase in agerelated diseases, which impair the quality of life of the elderly. The characteristic feature of aging is progressive physiological decline, which is the largest cause of human pathology and death worldwide. However, natural aging interacts in exceptionally complex ways within and between organs, but its underlying mechanisms are still poorly understood. Long non-coding RNA (lncRNA) is a type of noncoding RNA that exceeds 200 nucleotides in length and does not possess protein-coding ability. It plays a crucial role in the occurrence and development of diseases. ANRIL, also known as CDKN2B-AS1, is an antisense ncRNA located at the INK4 site. It can play a crucial role in agerelated disease progression by regulating single nucleotide polymorphism, histone modifications, or post-transcriptional modifications (such as RNA stability and microRNA), such as cardiovascular disease, diabetes, tumor, arthritis, and osteoporosis. Therefore, a deeper understanding of the molecular mechanisms of lncRNA ANRIL in age-related diseases will help provide new diagnostic and therapeutic targets for clinical practice.

Multi-omics analysis revealed that the protein kinase MoKin1 affected the cellular response to endoplasmic reticulum stress in the rice blast fungus, Magnaporthe oryzae.

BACKGROUND: Previous studies have shown that protein kinase MoKin1 played an important role in the growth, conidiation, germination and pathogenicity in rice blast fungus, Magnaporthe oryzae. ΔMokin1 mutant showed significant phenotypic defects and significantly reduced pathogenicity. However, the internal mechanism of how MoKin1 affected the development of physiology and biochemistry remained unclear in M. oryzae. RESULT: This study adopted a multi-omics approach to comprehensively analyze MoKin1 function, and the results showed that MoKin1 affected the cellular response to endoplasmic reticulum stress (ER stress). Proteomic analysis revealed that the downregulated proteins in ΔMokin1 mutant were enriched mainly in the response to ER stress triggered by the unfolded protein. Loss of MoKin1 prevented the ER stress signal from reaching the nucleus. Therefore, the phosphorylation of various proteins regulating the transcription of ER stress-related genes and mRNA translation was significantly downregulated. The insensitivity to ER stress led to metabolic disorders, resulting in a significant shortage of carbohydrates and a low energy supply, which also resulted in severe phenotypic defects in ΔMokin1 mutant. Analysis of MoKin1-interacting proteins indicated that MoKin1 really took participate in the response to ER stress. CONCLUSION: Our results showed the important role of protein kinase MoKin1 in regulating cellular response to ER stress, providing a new research direction to reveal the mechanism of MoKin1 affecting pathogenic formation, and to provide theoretical support for the new biological target sites searching and bio-pesticides developing.

Osteoinductive micro-nano guided bone regeneration membrane for in situ bone defect repair.

BACKGROUND: Biomaterials used in bone tissue engineering must fulfill the requirements of osteoconduction, osteoinduction, and osseointegration. However, biomaterials with good osteoconductive properties face several challenges, including inadequate vascularization, limited osteoinduction and barrier ability, as well as the potential to trigger immune and inflammatory responses. Therefore, there is an urgent need to develop guided bone regeneration membranes as a crucial component of tissue engineering strategies for repairing bone defects. METHODS: The mZIF-8/PLA membrane was prepared using electrospinning technology and simulated body fluid external mineralization method. Its ability to induce biomimetic mineralization was evaluated through TEM, EDS, XRD, FT-IR, zeta potential, and wettability techniques. The biocompatibility, osteoinduction properties, and osteo-immunomodulatory effects of the mZIF-8/PLA membrane were comprehensively evaluated by examining cell behaviors of surface-seeded BMSCs and macrophages, as well as the regulation of cellular genes and protein levels using PCR and WB. In vivo, the mZIF-8/PLA membrane's potential to promote bone regeneration and angiogenesis was assessed through Micro-CT and immunohistochemical staining. RESULTS: The mineralized deposition enhances hydrophilicity and cell compatibility of mZIF-8/PLA membrane. mZIF-8/PLA membrane promotes up-regulation of osteogenesis and angiogenesis related factors in BMSCs. Moreover, it induces the polarization of macrophages towards the M2 phenotype and modulates the local immune microenvironment. After 4-weeks of implantation, the mZIF-8/PLA membrane successfully bridges critical bone defects and almost completely repairs the defect area after 12-weeks, while significantly improving the strength and vascularization of new bone. CONCLUSIONS: The mZIF-8/PLA membrane with dual osteoconductive and immunomodulatory abilities could pave new research paths for bone tissue engineering.

Domain wall magnetic tunnel junction-based artificial synapses and neurons for all-spin neuromorphic hardware.

We report a breakthrough in the hardware implementation of energy-efficient all-spin synapse and neuron devices for highly scalable integrated neuromorphic circuits. Our work demonstrates the successful execution of all-spin synapse and activation function generator using domain wall-magnetic tunnel junctions. By harnessing the synergistic effects of spin-orbit torque and interfacial Dzyaloshinskii-Moriya interaction in selectively etched spin-orbit coupling layers, we achieve a programmable multi-state synaptic device with high reliability. Our first-principles calculations confirm that the reduced atomic distance between 5d and 3d atoms enhances Dzyaloshinskii-Moriya interaction, leading to stable domain wall pinning. Our experimental results, supported by visualizing energy landscapes and theoretical simulations, validate the proposed mechanism. Furthermore, we demonstrate a spin-neuron with a sigmoidal activation function, enabling high operation frequency up to 20 MHz and low energy consumption of 508 fJ/operation. A neuron circuit design with a compact sigmoidal cell area and low power consumption is also presented, along with corroborated experimental implementation. Our findings highlight the great potential of domain wall-magnetic tunnel junctions in the development of all-spin neuromorphic computing hardware, offering exciting possibilities for energy-efficient and scalable neural network architectures.

IGFBP2 induces podocyte apoptosis promoted by mitochondrial damage via integrin α5/FAK in diabetic kidney disease.

Podocyte apoptosis or loss is the pivotal pathological characteristic of diabetic kidney disease (DKD). Insulin-like growth factor-binding protein 2 (IGFBP2) have a proinflammatory and proapoptotic effect on diseases. Previous studies have shown that serum IGFBP2 level significantly increased in DKD patients, but the precise mechanisms remain unclear. Here, we found that IGFBP2 levels obviously increased under a diabetic state and high glucose stimuli. Deficiency of IGFBP2 attenuated the urine protein, renal pathological injury and glomeruli hypertrophy of DKD mice induced by STZ, and knockdown or deletion of IGFBP2 alleviated podocytes apoptosis induced by high concentration of glucose or in DKD mouse. Furthermore, IGFBP2 facilitated apoptosis, which was characterized by increase in inflammation and oxidative stress, by binding with integrin α5 (ITGA5) of podocytes, and then activating the phosphorylation of focal adhesion kinase (FAK)-mediated mitochondrial injury, including membrane potential decreasing, ROS production increasing. Moreover, ITGA5 knockdown or FAK inhibition attenuated the podocyte apoptosis caused by high glucose or IGFBP2 overexpression. Taken together, these findings unveiled the insight mechanism that IGFBP2 increased podocyte apoptosis by mitochondrial injury via ITGA5/FAK phosphorylation pathway in DKD progression, and provided the potential therapeutic strategies for diabetic kidney disease.

Synergetic Responses of Multiple Functions Induced by Phase Transition in Molecular Materials.

Materials that integrate magnetism, electricity and luminescence can not only improve the operational efficiency of devices, but also potentially generate new functions through their coupling. Therefore, multifunctional synergistic effects have broad application prospects in fields such as optoelectronic devices, information storage and processing, and quantum computing. However, in the research field of molecular materials, there are few reports on the synergistic multifunctional properties. The main reason is that there is insufficient awareness of how to obtain such material. In this brief review, we summarized the molecular materials with this characteristic. The structural phase transition of substances will cause changes in their physical properties, as the electronic configurations of the active unit in different structural phases are different. Therefore, we will classify and describe the multifunctional synergistic complexes based on the structural factors that cause the first-order phase transition of the complexes. This enables us to quickly screen complexes with synergistic responses to these properties through structural phase transitions, providing ideas for studying the synergistic response of physical properties in molecular materials.

The therapeutic effect of traditional Chinese medicine on breast cancer through modulation of the Wnt/ß-catenin signaling pathway.

Breast cancer, the most prevalent malignant tumor among women globally, is significantly influenced by the Wnt/ß-catenin signaling pathway, which plays a crucial role in its initiation and progression. While conventional chemotherapy, the standard clinical treatment, suffers from significant drawbacks like severe side effects, high toxicity, and limited prognostic efficacy, Traditional Chinese Medicine (TCM) provides a promising alternative. TCM employs a multi-targeted therapeutic approach, which results in fewer side effects and offers a high potential for effective treatment. This paper presents a detailed analysis of the therapeutic impacts of TCM on various subtypes of breast cancer, focusing on its interaction with the Wnt/ß-catenin signaling pathway. Additionally, it explores the effectiveness of both monomeric and compound forms of TCM in the management of breast cancer. We also discuss the potential of establishing biomarkers for breast cancer treatment based on key proteins within the Wnt/ß-catenin signaling pathway. Our aim is to offer new insights into the prevention and treatment of breast cancer and to contribute to the standardization of TCM.

Artificial intelligence for gastric cancer in endoscopy: From diagnostic reasoning to market.

Recognition of gastric conditions during endoscopy exams, including gastric cancer, usually requires specialized training and a long learning curve. Besides that, the interobserver variability is frequently high due to the different morphological characteristics of the lesions and grades of mucosal inflammation. In this sense, artificial intelligence tools based on deep learning models have been developed to support physicians to detect, classify, and predict gastric lesions more efficiently. Even though a growing number of studies exists in the literature, there are multiple challenges to bring a model to practice in this field, such as the need for more robust validation studies and regulatory hurdles. Therefore, the aim of this review is to provide a comprehensive assessment of the current use of artificial intelligence applied to endoscopic imaging to evaluate gastric precancerous and cancerous lesions and the barriers to widespread implementation of this technology in clinical routine.

Influence of topography and synoptic weather patterns on air quality in a valley basin city of Northwest China.

To clarify the mechanism underlying the effects of weather patterns and topography on air pollution, this study conducted the obliquely rotated principal component analysis in the T-mode to analyze ERA5 reanalysis data and categorize typical weather patterns at a 700-hPa geopotential height from 2015 to 2022. The probability of worsened air pollution attributable to weather patterns was quantitatively assessed using a generalized additive model. The results indicated that due to the influence of topography, Lanzhou was affected by an extended period of downdraft (with weak convective intensity) and the delayed formation of a convective boundary layer during the daytime by 1-2 h relative to other areas. Under the combined effect of low trough patterns (south low pressure type [SL] and south low weak pressure type [SL-]) and topography, the formation of a stable layer above the planetary boundary layer (PBL) would weaken the vertical exchange of the local airflow and inhibit the development of the PBL. The type of SL led to the most severe pollution, causing a 61.9 % (95 % confidence interval [CI]: 46.3 %-79.3 %) increase in PM2.5 concentration. For southwest high pressure patterns (south high [SH], southwest weak high [SWH-], southwest high [SWH], and southwest strong high [SWH+] pressure types), the prevailing northwest wind was the main transport path for pollutants. For the high pressure patterns (north high [NH] and northwest high [NWH] pressure types) and south wind patterns (southeast weak high [SEH-], southeast high [SEH], and northeast high [NEH] pressure types), the enhancement of vertical convection, deepening of the PBL, and reduction of pollution transport led to improved air quality. The NH, NWH, and NEH pressure types caused PM2.5 concentration to decrease by 18.4 % (95 % CI: 8.8 %-27.1 %), 14.9 % (95 % CI: 4.7 %-24.0 %), and 35.9 % (95 % CI: 9.7 %-54.6 %), respectively.

Prevalence, correlates, and mental health outcomes of social jetlag in Chinese school-age adolescents: A large-scale population-based study.

BACKGROUND: This cross-sectional study aimed to examine the prevalence and correlates of social jetlag (SJL) in Chinese adolescents, as well as to test the relationships between SJL and mental health problems. METHODS: A total of 106979 students (Mage = 13.0 ± 1.8 years; Nmale = 58296 [54.5 %]) from Shenzhen, China completed an online survey from May 24th to June 5th, 2022. Information on sociodemographics, lifestyles, sleep characteristics, anxiety symptoms, and depressive symptoms was collected by a self-administered questionnaire. Multivariate and binary logistic regression were adopted for data analysis. RESULTS: 17.8 % of participants experienced SJL ≥ 2 h. To adjust the accumulated sleep debt, sleep-corrected SJL (SJLsc) was calculated and 8.3 % of individuals self-reported SJLsc ≥ 2 h. Both SJL and SJLsc show an increasing trend with age. Risk factors of SJL included females, poor parental marital status, being overweight, physically inactive, smoking, drinking, and having a late chronotype. Moreover, males, having siblings, boarding at school, short sleep duration, experiencing insomnia, and frequent nightmares were significantly associated with an increased risk of SJLsc. After adjusting for all covariates, adolescents with SJLsc ≥ 2 h were more likely to have anxiety symptoms (OR: 1.35, 95 % CI: 1.24-1.48) and depressive symptoms (OR: 1.35, 95 % CI: 1.25-1.46) than those with SJLsc < 1 h. CONCLUSIONS: SJL is common among Chinese school-age adolescents. This study is valuable for the development of prevention and intervention strategies for SJL in adolescents at the population level. Additionally, the strong links between SJLsc and emotional problems underscore the critical significance of addressing SJL as a key aspect of adolescent well-being.

Microsphere-Structured Protein Hydrogel Dielectrics for Capacitive Wearable Sensors.

The desire for healthy living has created a crucial need for portable flexible health-monitoring devices based on biomaterials. Toward this end, we report a microsphere-structured hydrogel that uses bovine serum albumin (BSA) as a dielectric layer for capacitive pressure sensors. We developed a theoretical model that describes how stacking dielectric layers of spheres affects the performance of capacitive sensors. We also prepared a prototype sensor featuring the unique microsphere structure to create capacitive sensors with high sensitivity (360.91 strain sensitivity), excellent cyclical stability, and a long service life (over 5000 stretching-compression cycles). Furthermore, the design of the hydrogel sensor allows for easy integration into fabrics to create devices such as smart wristbands, which can collect a diverse range of health data. Thus, BSA-hydrogel-based sensors not only provide safe wearable devices but also advance the performance of high-sensitivity capacitive sensors.

Long noncoding RNA AI504432 upregulates FASN expression by sponging miR-1a-3p to promote lipogenesis in senescent adipocytes.

Aging affects lipid metabolism and can cause obesity as it is closely related to the disorder of many lipogenic regulatory factors. LncRNAs have been recognized as pivotal regulators across diverse biological processes, but their effects on lipogenesis in aging remain to be further studied. In this work, using RNA sequencing (RNA-Seq), we found that the expression of lncRNA AI504432 was significantly upregulated in the eWAT (epididymal white adipose tissue) of aging mice, and the knockdown of AI504432 notably reduced the expression of several adipogenic genes (e.g., Cebp/α, Srebp-1c, Fasn, Acaca, and Scd1) in senescent adipocytes. The bioinformatics investigation revealed that AI504432 possessed a binding site for miR-1a-3p, and the discovery was verified by the luciferase reporter assay. The expression of Fasn was increased upon the inhibition of miR-1a-3p but restored upon the simultaneous silencing of AI504432. Taken together, our results suggested that AI504432 controlled lipogenesis through the miR-1a-3p/Fasn signaling pathway. The findings may inspire new therapeutic approaches to target imbalanced lipid homeostasis due to aging.

Phosphaturic mesenchymal tumor-induced bilateral osteomalacia femoral neck fractures: a case report.

Phosphaturic mesenchymal tumors (PMT) are rare and distinctive tumors that typically result in paraneoplastic syndrome known as tumor-induced osteomalacia (TIO). We report a case of bilateral osteoporotic femoral neck fracture caused by PMT. PMT was surgically resected, followed by sequential treatment of bilateral femoral neck fractures with total hip arthroplasty (THA). A 49-year-old perimenopausal woman experienced consistent bone pain with limb weakness persisting for over 2 years. Initially, she was diagnosed with early osteonecrosis of the femoral head and received nonsurgical treatment. However, from 2020 to 2022, her pain extended to the bilateral shoulders and knees with increased intensity. She had no positive family history or any other genetic diseases, and her menstrual cycles were regular. Physical examination revealed tenderness at the midpoints of the bilateral groin and restricted bilateral hip range of motion, with grade 3/5 muscle strength in both lower extremities. Laboratory findings revealed moderate anemia (hemoglobin 66 g/L), leukopenia (2.70 × 109/L), neutropenia (1.28 × 109/L), hypophosphatemia (0.36 mmol/L), high alkaline phosphatase activity (308.00 U/L), and normal serum calcium (2.22 mmol/L). After surgery, additional examinations were performed to explore the cause of hypophosphatemic osteomalacia. After definitive diagnosis, the patient underwent tumor resection via T11 laminectomy on August 6, 2022. Six months after the second THA, the patient regained normal gait with satisfactory hip movement function without recurrence of PMT-associated osteomalacia or prosthesis loosening. By providing detailed clinical data and a diagnostic and treatment approach, we aimed to improve the clinical understanding of femoral neck fractures caused by TIO.

Cancer progression and tumor hypercoagulability: a platelet perspective.

Venous thromboembolism, which is common in cancer patients and accompanies or even precedes malignant tumors, is known as cancer-related thrombosis and is an important cause of cancer- associated death. At present, the exact etiology of the elevated incidence of venous thrombosis in cancer patients remains elusive. Platelets play a crucial role in blood coagulation, which is intimately linked to the development of arterial thrombosis. Additionally, platelets contribute to tumor progression and facilitate immune evasion by tumors. Tumor cells can interact with the coagulation system through various mechanisms, such as producing hemostatic proteins, activating platelets, and directly adhering to normal cells. The relationship between platelets and malignant tumors is also significant. In this review article, we will explore these connections.

De novo transcriptome assembly database for 100 tissues from each of seven species of domestic herbivore.

Domesticated herbivores are an important agricultural resource that play a critical role in global food security, particularly as they can adapt to varied environments, including marginal lands. An understanding of the molecular basis of their biology would contribute to better management and sustainable production. Thus, we conducted transcriptome sequencing of 100 to 105 tissues from two females of each of seven species of herbivore (cattle, sheep, goats, sika deer, horses, donkeys, and rabbits) including two breeds of sheep. The quality of raw and trimmed reads was assessed in terms of base quality, GC content, duplication sequence rate, overrepresented k-mers, and quality score distribution with FastQC. The high-quality filtered RNA-seq raw reads were deposited in a public database which provides approximately 54 billion high-quality paired-end sequencing reads in total, with an average mapping rate of ~93.92%. Transcriptome databases represent valuable resources that can be used to study patterns of gene expression, and pathways that are related to key biological processes, including important economic traits in herbivores.

Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer.

BACKGROUND: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive. METHODS: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC. RESULTS: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer. CONCLUSIONS: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients. KEY POINTS: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.