Xuefeng Zhou

Defective mitophagy is a key pathological risk of Alzheimer’s disease (AD), yet available pharmacological agents capable of restoring mitophagy remain clinically limited, largely due to the lack of tools for drug screening and target identification. To address this, we introduce an integrated platform with three novel artificial intelligence (AI)-enabled approaches—the phenotype-based screening model ‘CellAutoFM’, the drug-likeness predictor ‘ADMET Ranker’, and the target deconvolution method ‘PROCAT’. Using this platform together with wet lab validation, Crassifolin A (JGX-1) is identified as a potent natural product-derived mitophagy inducer; structurally, JGX-1 directly binds to ATP-binding cassette sub-family A member 1 (ABCA1) and sub-family G member 1 (ABCG1), triggering enhanced cholesterol efflux which activates PINK1/Parkin-dependent mitophagy. In both in vitro and in vivo AD laboratory models, JGX-1 reduces amyloid-β and Tau pathologies in an autophagy/mitophagy-dependent manner as these benefits are dramatically blunted with key mitophagy genes knocked down. Collectively, we provide an open-access, reproducible AI-assisted platform for rapid compound screening, drug-likeness evaluation, and potential target prediction to advance drug discovery. Through this paradigm, we unveil modulating the ABCA1/ABCG1-mediated cholesterol-mitophagy pathway as a promising anti-AD strategy, with a novel drug candidate JGX-1 identified.

Background: Acute lung injury (ALI) is a common inflammatory pulmonary disorder, with increasing evidence implicating ferroptosis as a critical type of cell death in its pathogenesis. Ubiquitin‐specific protease 43 (USP43) is an important deubiquitinating enzyme that plays a significant role in both inflammation and ferroptosis regulation. In this study, we mainly analysed whether USP43 could participate in the process of ALI by regulating the ferroptosis process, and clarified its molecular mechanism. Methods: To investigate the functional role of USP43 in ALI, Usp43 knockout mice, USP43 knockdown and overexpressed human bronchial epithelial BEAS‐2B cells and mouse alveolar type II epithelial MLE12 cells were treated with lipopolysaccharide (LPS) in vivo and in vitro. Subsequently, ferroptosis inhibitor and activator, Ferrostatin‐1 and Erastin, were taken to explore the effect of ferroptosis on the regulation function of USP43 in ALI. Finally, co‐immunoprecipitation (Co‐IP), ubiquitination and rescue assays were conducted to determine the regulation mechanism of USP43. Results: The expression of USP43 was up‐regulated during ALI. Usp43 ‐KO mice exhibited aggravated lung injury, inflammation and ferroptosis. Consistently, USP43 knockdown exacerbated LPS‐stimulated cellular damage, inflammation and ferroptosis, while its overexpression exerted the opposite effect in vitro. Furthermore, the regulation effects of USP43 on ALI mainly depended on ferroptosis by administering a ferroptosis inducer and inhibitor, respectively. Mechanistically, USP43 was found to inhibit K48‐linked polyubiquitination of solute carrier family 7 member 11 (SLC7A11), thereby stabilising SLC7A11. Overexpression of SLC7A11 rescued the ferroptosis, cellular and lung tissue injury and inflammation aggravated by USP43 knockdown or deficiency. Conclusion: USP43 prevents the progression of ALI by mediating K48‐linked deubiquitination of SLC7A11, thereby inhibiting ferroptosis. Targeting USP43 may represent a potential therapeutic strategy for ALI treatment by enhancing SLC7A11 stability and inhibiting ferroptosis. Key points: USP43 has been proven to be upregulated during LPS‐induced ALI. This study is the first to demonstrate that USP43 can inhibit the progression of LPS‐induced ALI by suppressing ferroptosis. This study proved that USP43 can interects with SLC7A11 and removes the K48‐linked ubiquitinaiton of SLC7A11, thereby enhances the stability of it and subsequently inhibiting ferroptosis during the LPS-induced ALI process. The regulation of USP43 on LPS‐induced ALI mainly depends on SLC7A11, and USP43 is expected to become a new target for the treatment of ALI/ADRS.

Introduction: Acute lung injury (ALI) remains a lethal clinical challenge driven by an uncontrolled “cytokine storm” resulting from dysregulated inflammatory networks. The metabolic and molecular mechanisms orchestrating this process remain incompletely understood. Methods: We integrated multi-omics profiling with functional analyses in murine models and human iPSC-derived alveolar organoids. Key molecular players were identified through loss-of-function and pharmacological interventions, and the effects of a dual-target strategy using progesterone (PT) and ethyl methanesulfonate (EMS) were evaluated. Results: Metabolic reprogramming-driven lactylation emerged as a central orchestrator of inflammatory progression. PDAP1 lactylation acts as a pivotal metabolic switch for NLRP3 inflammasome activation and selective IL-1β release. Functional deficiency of PDLIM1 releases the molecular brake on NF-κB signaling, precipitating a broad-spectrum inflammatory cascade. These modifications bridge metabolic stress with oxidative damage via the NRF2/GPX4-mediated ferroptotic pathway. The “dual-target, dual-drug” intervention—PT targeting the PDLIM1 axis and EMS selectively disrupting PDAP1-mediated IL-1β maturation—effectively quelled systemic inflammation and attenuated ALI pathology in both in vivo and organoid models. Discussion: This study elucidates a novel metabolic-immune coupling mechanism in pulmonary polarization, shifting the focus from pan-inflammatory suppression toward precision immunomodulation. The findings provide a transformative theoretical paradigm for the management of ALI.

We explored the sex difference in lung ischemia–reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α.

Background: This research focuses on the relationship between the changes in peripheral blood eosinophils (PBEs) perioperatively and the prognosis of lung cancer. Methods: The study included 414 lu...

Background: The fatality rate of acute lung injury (ALI) is as high as 40% to 60%. Although various factors, such as sepsis, trauma, pneumonia, burns, blood transfusion, cardiopulmonary bypass, and pancreatitis, can induce ALI, patients with these risk factors will eventually develop ALI. The rate of developing ALI is not high, and the outcomes of ALI patients vary, indicating that it is related to genetic differences between individuals. In a previous study, we found multiple functions of cavin-2 in lung function. In addition, many other studies have revealed that CAV1 is a critical regulator of lung injury. Due to the strong relationship between cavin-2 and CAV1, we suspect that cavin-2 is also associated with ALI. Furthermore, we are curious about the role of the CAV family and cavin family genes in ALI. Methods: To reveal the mechanism of CAV and CAVIN family genes in ALI, we propose DeepGENE to predict whether CAV and CAVIN family genes are associated with ALI. This method constructs a gene interaction network and extracts gene expression in 84 tissues. We divided these features into two groups and used two network encoders to encode and learn the features. Results: Compared with DNN, GBDT, RF and KNN, the AUC of DeepGENE increased by 7.89%, 16.84%, 20.19% and 32.01%, respectively. The AUPR scores increased by 8.05%, 15.58%, 22.56% and 23.34%. DeepGENE shows that CAVIN-1, CAVIN-2, CAVIN-3 and CAV2 are related to ALI. Conclusion: DeepGENE is a reliable method for identifying acute lung injury-related genes. Multiple CAV and CAVIN family genes are associated with acute lung injury-related genes through multiple pathways and gene functions.

Acute respiratory distress syndrome (ARDS) gives rise to uncontrolled inflammatory response and oxidative stress, causing very high mortality globally. Pomiferin is a kind of prenylated isoflavonoid extracted from Maclura pomifera, owning anti‐inflammatory and antioxidant properties. However, the functions and possible mechanisms of pomiferin in lipopolysaccharide‐ (LPS‐) induced ARDS remain unknown. C57BL/6 mice were injected with LPS (5 mg/kg) intratracheally to induce an in vivo ARDS model while RAW264.7 macrophages were stimulated with LPS (100 ng/ml) to induce an in vitro model. Our data demonstrated that pomiferin (20 mg/kg) significantly improved pulmonary function and lung pathological injury in mice with ARDS, apart from increasing survival rate. Meanwhile, pomiferin treatment also inhibited LPS‐induced inflammation as well as oxidative stress in lung tissues. LPS stimulation significantly activated AKT/Foxo1 signal pathway in lung tissues, which could be reversed after pomiferin treatment. In vitro experiments further showed that 10, 20, and 50 μM of pomiferin could enhance cell viability of RAW264.7 macrophages stimulated with LPS. What is more, 3‐deoxysappanchalcone (3‐DE), one AKT agonist, was used to active AKT in RAW264.7 macrophages. The results further showed that 3‐DE could abolish pomiferin‐elicited protection in LPS‐treated RAW264.7 macrophages, evidenced by activated inflammation and oxidative stress. Taken together, our study showed that pomiferin could exert an ARDS‐protective effect by blocking the AKT/Foxo1 signal pathway to inhibit LPS‐induced inflammatory response and oxidative injury, which may serve as a potential candidate for the treatment of ARDS in the future.

Purpose: The International Association for the Study of Lung Cancer (IASLC) of TNM staging system has been well accepted as a precise model. However, the latest American Joint Committee on Cancer (AJCC) staging system to solve the different survival and prognosis of lung adenocarcinoma in the same period is still controversial. Therefore, it is necessary to thoroughly explore the applicability between the new system and survival prediction in terms of lung adenocarcinoma. Methods: We recruited 52,517 patients with lung adenocarcinoma from the Surveillence, Epidemiology, and End Results database. Cox regression analysis was performed to determine survival related factors. The mortality rate per 1000 persons per year of the T4N2M0 lung adenocarcinoma stage and other stages were compared. Survival curves were obtained using the Kaplan-Meier analysis and log-rank test. Results: The results of Cox proportional hazards regression analysis showed that age at diagnosis, race, T stage, distant metastasis, extrathoracic extension, radiotherapy, chemotherapy, and surgery are independent factors related to cancer-specific survival (CSS) and all-cause survival. Furthermore, patients with stage IIIA disease (PP0.05). Conclusion: The survival rate of patients with T4N2M0 stage was significantly lower than that of patients with IIIA and IIIB stages excluding T4N2M0, there was no significant difference between T4N2M0 and IIIC. It was suggested that this group of patients with stage T4N2M0 were upgraded in the 8th IASLC system.

Research points out that it is particularly important to comprehensively evaluate immune microenvironmental indicators and gene mutation characteristics to select the best treatment plan. Therefore, exploring the relevant genes of pulmonary injury is an important basis for the improvement of survival. In recent years, with the massive production of omics data, a large number of computational methods have been applied in the field of biomedicine. Most of these computational methods are devel-oped for a certain type of diseases or whole diseases. Algorithms that specifically identify genes associated with pulmonary injury have not yet been developed. To fill this gap, we developed a novel method, named AdaRVM, to identify pulmonary injury-related genes in large scale. AdaRVM is the fusion of Adaboost and Relevance Vector Machine (RVM) to achieve fast and high-precision pattern recognition of pulmonary injury genetic mechanism. AdaRVM found that Cavin-2 gene has strong potential to be related to pulmonary injury. As we known, the formation and function of Caveolae are mediated by two family proteins: Caveolin and Cavin. Many studies have explored the role of Caveolin proteins, but people still knew little about Cavin family members. To verify our method and reveal the functions of cavin-2, we integrated six genome-wide association studies (GWAS) data related to lung function traits, four expression Quantitative Trait Loci (eQTL) data, and one methylation Quantitative Trait Loci (mQTL) data by Summary data level Mendelian Randomization (SMR). We found strong relationship between cavin-2 and canonical signaling pathways ERK1/2, AKT, and STAT3 which are all known to be related to lung injury.