IntroductionHericenone C exhibits antinociceptive effects in inflammatory pain; however, its molecular target and underlying mechanism remain unclear.Methods and ResultsWe assessed the effect of hericenone C on formalin-induced nociceptive behavior in mice and explored its molecular target using in vitro experiments. Based on competitive affinity proteomics, we identified direct interactions between RORα and hericenone C; functional assays confirmed the role of hericenone C as a RORα antagonist that suppresses RORE-mediated transcriptional activity. Integrated bioinformatics and experimental validation indicated hericenone C-mediated suppression of TLR4 expression via inhibited RORα binding to the TLR4 promoter, which attenuates NF-κB signaling. This mechanism was further validated through pharmacological and genetic approaches, revealing that hericenone C and RORα antagonist SR3335 synergistically modulate TLR4 expression in RORα-modified macrophages. In the formalin-induced nociceptive pain model mice, formalin activated NF-κB through TLR4-dependent P65 phosphorylation, while macrophage depletion selectively suppressed phase 2 nociception. Critically, adoptive transfer of RORα-overexpressing or SR1078-pretreated monocyte-enriched PBMCs exacerbated pain, which was effectively reversed by hericenone C. Notably, hericenone C pretreatment reduced CD11c+ cell infiltration and decreased TLR4 expression in inflamed paw tissues.ConclusionOverall, these findings establish hericenone C as a novel RORα antagonist that alleviates inflammatory pain through inhibition of the RORα-TLR4-NF-κB axis in CD11c+ cells, offering a promising therapeutic strategy for pain management.

ETHNOPHARMACOLOGICAL RELEVANCE:Postoperative wound healing, especially after anal-fistula surgery, poses unique clinical challenges due to the complex anal anatomy and the need for accelerated recovery. Although the ethnomedicinal plant Cayratia japonica (Thunb.) Gagnep. has long been recognized for its wound-healing properties, its molecular basis and therapeutic potential remain poorly defined. Here, an optimized C. japonica hydrogel (CJH) markedly improved clinical outcomes, while temporal multi-omics profiling underscored the necessity of stage-specific therapeutic adaptation. Specifically, CJH-derived Luteolin 7-glucuronide was found to enhance fibroblast proliferation via BMP4 protein engagement and downstream signaling activation, thereby accelerating wound remodeling. PURPOSE OF RESEARCH:This study developed an innovative CJH and systematically investigated its molecular mechanisms in skin wound healing through integrated multi-omics analyses. MATERIALS AND METHODS:CJH was optimized through single-factor screening and characterized by scanning electron microscopy and spectroscopic analyses. A prospective randomized controlled trial (n = 81) was conducted to evaluate its clinical efficacy. Transcriptomic datasets (GSE28914, GSE241132) were analyzed using time-series clustering and underwent a comprehensive weighted gene co-expression network analysis (WGCNA), including gene expression matrix standardization, soft-thresholds selection, modules construction, and module-trait correlation analysis, to identify key temporal gene modules. Single-cell RNA sequencing was further to employed to elucidate cell-type-specific gene expression patterns. Ultra-performance liquid chromatography - electrospray ionization - quadrupole time-of-flight - tandem mass spectrometry (UPLC-ESI-Q-TOF-MS/MS), combined with Global Natural Products Social Molecular Networking (GNPS), was used to identify active compounds, followed by molecular docking and in vitro validation. RESULTS:CJH significantly improved wound healing compared with control (healing rate 68.5 ± 12.3% vs 45.2 ± 15.7%, P < 0.001) and shortened recovery time (P = 0.031). Multi-omics analysis of public human cutaneous wound datasets identified three phase-associated hubs: OASL for the acute immune phase, TIMP3 for the early repair phase, and BMP4 for the remodeling phase. These findings highlight a stage-specific molecular program in skin wound healing. Among these candidates, BMP4 was prioritized for experimental validation due to its temporal concordance with the clinical treatment window. UPLC-ESI-Q-TOF-MS/MS was used to identify the chemical constituents of CJH, among which Luteolin 7-glucuronide was subsequently predicted by molecular docking to be a key bioactive compound capable of binding BMP4 (binding energy -8.2 kcal/mol). In vitro assays demonstrated that Luteolin 7-glucuronide engaged the BMP4 protein, enhanced its thermal stability, and potentiated downstream Smad signaling, accompanied by increased fibroblast proliferation. CONCLUSION:CJH enhanced clinical wound healing following anal fistula surgery. Skin-derived temporal programs identify TIMP3, OASL, and BMP4 as stage-associated regulators, while perianal tissue readouts together with in vitro assays support BMP4 protein engagement and pathway activation as a likely mechanism contributing to the observed repair benefits.

Asthma is a heterogeneous airway disease in which chronic inflammation, epithelial barrier injury, immune-cell imbalance and airway remodeling interact to shape variable clinical phenotypes. N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNA, has emerged as a dynamic epitranscriptomic layer that regulates RNA splicing, export, stability, translation and decay. Recent profiling studies and mechanistic experiments indicate that m6A patterns and m6A regulators are altered in lung tissue, airway epithelial cells, airway smooth muscle cells and immune cells in asthma. These changes influence type 2 inflammation, the balance between T helper 1 (Th1) and T helper 2 (Th2) cells, the balance between T helper 17 (Th17) and regulatory T (Treg) cells, macrophage polarization, epithelial ferroptosis, ciliary function, mitochondrial stress, pollutant responses and structural remodeling. This Review synthesizes current evidence linking m6A writers, erasers and readers to asthma pathobiology, highlights context-dependent and sometimes opposing functions of key regulators such as METTL3, FTO and ALKBH5, and discusses how m6A signatures may inform biomarker discovery and therapeutic development. We also outline major translational barriers, including cell-type specificity, target validation, assay standardization and safety of pharmacologic m6A modulation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening interstitial lung disorder marked by aberrant mucus hypersecretion and excessive extracellular matrix (ECM) deposition, which together severely limit the effectiveness of current therapies. Although inhalation therapy enables localized pulmonary drug delivery, pathological mucus accumulation and ECM stiffening jointly form a "traffic jam-like" physical obstruction that severely restricts drug penetration and retention. Here, we developed dual-enzyme-modified inhalable nanoparticles (Lipo/PFD-CB) by co-functionalizing the liposomal surface with bromelain and collagenase to synergistically overcome these obstructive barriers and enhance pulmonary delivery of the FDA-approved antifibrotic drug pirfenidone (PFD). Specifically, bromelain cleaves mucin crosslinks to reduce mucus viscosity, while collagenase degrades dense ECM fibers to facilitate deep tissue penetration and prolonged retention. This dual-enzyme remodeling strategy significantly improved aerosol deposition efficiency (86.5%) and optimized the pharmacokinetic profile and tissue distribution of PFD. In both early and advanced bleomycin-induced fibrosis models, Lipo/PFD-CB effectively attenuated profibrotic cellular activation and restored alveolar architecture and airflow. This study introduces an enzyme-mediated, microenvironment-remodeling inhalable nanoplatform that effectively "clears the pulmonary traffic jam," restoring airflow and tissue homeostasis and offering a promising strategy to enhance therapeutic outcomes in IPF.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening chronic progressive lung disease characterized by loss of alveolar function and excessive activation of fibroblasts, leading to continuous decline in pulmonary function. However, current therapies remain limited in efficacy, mainly due to the dysregulation between the airway and alveolar compartments. On one hand, airway epithelial cells migrate into alveolar spaces, resulting in bronchiolization and destruction of alveolar architecture. On the other hand, alveolar epithelial cells undergo epithelial-mesenchymal transition (EMT), supporting the activation of myofibroblasts and excessive deposition of extracellular matrix (ECM). Herein, we developed inhalable nanoparticles (Lipo-SN-R) capable of simultaneously inhibiting bronchiolarization and EMT, thereby alleviating alveolar dysfunction and excessive ECM deposition. Specifically, Lipo-SN-R was administered via nebulization into fibrotic lungs, where the RGDfC peptide enabled selective accumulation at injured regions. Subsequently, saracatinib suppressed bronchiolarization by blocking the formation of bronchoalveolar spheres, while nintedanib inhibited EMT and fibroblast overactivation. These combined effects synergistically restored airway-alveolar function and reestablished pulmonary homeostasis. This study demonstrates that such a therapeutic strategy aimed at restoring airway-alveolar homeostasis offers a promising avenue for improving IPF treatment outcomes and holds great potential for the treatment of various respiratory diseases.

Four previously unreported triterpenoids, ganolanoids A-D (1-4), were isolated from Ganoderma lucidum. Their structures, including relative and absolute configurations, were elucidated by IR, UV, HRESIMS, 1D/2D NMR, and X-ray crystallography. The antifibrotic potential of these compounds was evaluated in a TGF-β1-induced activation model using primary mouse lung fibroblasts (MLFs). Compounds 1-3 significantly suppressed the upregulation of the fibrosis marker α-SMA. To explore the underlying mechanism of the most active compound, ganolanoid A (1), an integrated computational approach combining network pharmacology, molecular docking, and 100-ns molecular dynamics simulations was employed, identifying estrogen receptor 1 (ESR1) as a potential target. Ganolanoid A exhibited strong and stable binding to ESR1 (binding energy: -63.85 kcal/mol). Experimental validation further demonstrated that ganolanoid A reversed TGF-β1-induced dysregulation of ESR1 protein expression. In summary, this study expands the chemical diversity of Ganoderma triterpenoids and reveals an ESR1-mediated mechanism by which ganolanoid A attenuates pulmonary fibrosis and supports its further investigation as a potential antifibrotic agent.

[This corrects the article DOI: 10.1016/j.apsb.2025.04.027.].

ETHNOPHARMACOLOGICAL RELEVANCE:Qufeng Xuanbi Formula (QFXBF), a traditional Chinese medicine prescription used for asthma-like respiratory disorders, has shown anti-asthmatic activity. However, whether it attenuates allergic airway remodeling through innate immune-metabolic regulation remains unknown. AIM OF THE STUDY:This study aimed to determine whether QFXBF alleviates house dust mite (HDM)-induced allergic airway inflammation and remodeling through targeting the STING/HIF-1α/glycolysis axis, and to evaluate the specific inhibitory potential of its constituent tectorigenin on STING-mediated immunometabolic signaling. MATERIALS AND METHODS:An HDM-induced allergic asthma model was established in male C57BL/6 mice by intranasal sensitization and challenge, followed by oral administration of QFXBF at 12.5, 25, and 50 g/kg/day or dexamethasone at 2 mg/kg/day. Airway hyperresponsiveness, lung histopathology, mucus secretion, collagen deposition, α-SMA expression, inflammatory mediators in BALF and serum, and glycolytic metabolic indices were evaluated. BSMCs were stimulated with IL-4 and LPS, both at 5 ng/mL, and treated with QFXBF at 2, 4, and 8 mg/mL. Cell proliferation, migration, glucose consumption, lactate production, RT-qPCR, Western blotting, and immunofluorescence were performed to assess airway smooth muscle activation and metabolic reprogramming. Transcriptomic analysis of lung tissue, STING overexpression, HIF-1α pharmacological inhibition, LC-MS/MS-based identification of tectorigenin, molecular docking, and molecular dynamics simulations were further used to investigate the STING/HIF-1α/glycolysis axis and the potential STING-targeting activity of tectorigenin. RESULTS:QFXBF markedly reduced airway hyperresponsiveness, inflammatory infiltration, and collagen deposition in HDM-challenged mice, accompanied by decreased asthma-related markers in bronchoalveolar lavage fluid and serum. QFXBF also downregulated STING, HIF-1α, and key glycolytic enzymes at both mRNA and protein levels in lung tissue. In IL-4+LPS-stimulated BSMCs, QFXBF dose-dependently suppressed proliferation and migration, reduced glucose utilization and lactate accumulation, and concurrently inhibited STING/HIF-1α and glycolysis-associated factors. Mechanistically, QFXBF attenuated HIF-1α activity and glycolytic flux through suppression of STING. Liquid chromatography-based analysis identified tectorigenin as a bioavailable constituent of QFXBF. In STING-overexpressing BSMCs, tectorigenin significantly reduced STING expression, proliferative activity, and lactate metabolism, supporting STING inhibition as a key pharmacological basis of QFXBF. CONCLUSION:QFXBF can alleviate allergic remodeling by suppressing the STING/HIF-1α-mediated glycolytic program. Tectorigenin may act as a potential STING inhibitor that disrupts innate immune-metabolic signaling, providing mechanistic support for QFXBF-derived therapeutic strategies in asthma.

Polysaccharides derived from Angelica dahurica exhibit potent wound healing activity, yet the pronounced structural heterogeneity of natural extracts has obscured the identity of the active motif and hindered clinical translation. Here we report a convergent, one-pot [22+22+22] glycosylation strategy based on glycosyl donor preactivation that enables the precise chemical synthesis of a 66-unit A. dahurica polysaccharide. This approach facilitates the efficient assembly of a comprehensive glycan library spanning tetrasaccharides to the full-length 66-mer polysaccharide, allowing for systematic biological evaluation. Functional screening identifies the reducing end hexasaccharide as the minimal active motif responsible for wound healing activity. Mechanistic analyses reveal that the synthetic hexa- and dodecasaccharides promote fibroblast and keratinocyte proliferation and migration, while concurrently reprogramming macrophage polarization. Crucially, gram-scale synthesis of both glycans enables definitive in vivo evaluation, demonstrating significantly accelerated wound closure through attenuation of excessive inflammation and promotion of organized collagen deposition. Collectively, these findings establish a general paradigm for deconvoluting heterogeneous natural polysaccharide extracts through de novo synthesis of structurally well-defined glycans as precision-engineered wound healing therapeutics.

Germplasm resources embody the genetic diversity of plants and form the foundation for breeding and the ongoing improvement of elite cultivars. The establishment of germplasm banks, along with their systematic evaluation, constitutes a critical step toward the conservation, sustainable use, and innovative utilization of these resources. Liriodendron, a rare and endangered tree genus with species distributed in both East Asia and North America, holds considerable ecological, ornamental, and economic significance. However, a standardized evaluation system for Liriodendron germplasm remains unavailable. In this study, 297 Liriodendron germplasm accessions were comprehensively evaluated using 34 phenotypic traits and whole-genome resequencing data. Substantial variation was observed in most phenotypic traits, with significant correlations identified among several characteristics. Cluster analysis based on phenotypic data grouped the accessions into three distinct clusters, each exhibiting unique distribution patterns. This classification was further supported by principal component analysis (PCA), which effectively captured the underlying variation among accessions. These phenotypic groupings demonstrated high consistency with subsequent population structure analysis based on SNP markers (K = 3). Notably, several key traits exhibited significant divergence (p < 0.05) among distinct genetic clusters, thereby validating the coordinated association between phenotypic variation and molecular markers. Genetic diversity and population structure were assessed using 4204 high-quality single-nucleotide polymorphism (SNP) markers obtained through stringent filtering. The results indicated that the Liriodendron sino-americanum displayed the highest genetic diversity, with an expected heterozygosity (He) of 0.18 and a polymorphic information content (PIC) of 0.14. In addition, both hierarchical clustering and PCA revealed clear population differentiation among the accessions. Association analysis between three phenotypic traits (DBH, annual height increment, and branch number) and SNPs identified 25 highly significant SNP loci (p < 0.01). Of particular interest, the branch number-associated locus SNP_17_69375264 (p = 1.03 × 10−5) demonstrated the strongest association, highlighting distinct genetic regulation patterns among different growth traits. A minimal set of 13 core SNP markers was subsequently used to construct unique DNA fingerprints for all 297 accessions. In conclusion, this study systematically characterized phenotypic traits in Liriodendron, identified high-quality and core SNPs, and established correlations between key phenotypic and molecular markers. These achievements enabled differential analysis and genetic diversity assessment of Liriodendron germplasm, along with the construction of DNA fingerprint profiles. The results provide crucial theoretical basis and technical support for germplasm conservation, accurate identification, and utilization of Liriodendron resources, while offering significant practical value for variety selection, reproduction and commercial applications of this species.

The increasing concentration of nanoplastics in the atmosphere has raised significant concerns regarding their biological toxicity. The toxicity of nanoplastics is often influenced by the surface charge they acquire in complex atmospheric environments. However, the mechanisms underlying lung toxicity from positively charged nanoplastics remain poorly understood, and effective pharmacological prevention and treatment strategies are lacking. This study aimed to investigate the pulmonary toxicity mechanisms of 100 nm amino-modified polystyrene nanoplastics (APS-NPs) using in vivo and in vitro models. In vivo, mice exposed to APS-NPs via inhalation exhibited oxidative stress and ferroptosis in lung tissues. Transcriptomic analysis revealed 566 differentially expressed mRNAs in the APS-NPs group compared to controls, primarily associated with 69 KEGG pathways. These findings suggest that APS-NPs induce ferroptosis in pulmonary tissues by inhibiting the Bmal1/Nrf2/HO-1 signaling cascade. In vitro, APS-NPs-induced ferroptosis in MLE-12 cells was significantly exacerbated by silencing the Bmal1 gene. Intriguingly, pre-treatment with mogrol (Mg), a natural Bmal1 agonist, protected against APS-NPs-induced lung toxicity. Our study provides new insights into the mechanisms of nanoplastic-induced lung toxicity, highlighting the role of disrupted circadian transcription factors like Bmal1 in driving ferroptosis and proposing potential intervention strategies to mitigate lung damage.

BACKGROUND:Pulmonary fibrosis (PF) is a chronic, lethal lung disease marked by permanent alterations to the lung tissue architecture. Although nintedanib (NDN) has been approved for clinical use, its therapeutic potential is substantially hampered by severe gastrointestinal side effects, notably diarrhea, which compromise patient adherence and quality of life. PURPOSE:This study aimed to investigate whether heterophyllin B (HB) could augment the antifibrotic efficacy of NDN while mitigating its gastrointestinal toxicity. METHODS:The therapeutic potential of HB was evaluated in a bleomycin (BLM)-induced murine model of PF. Alterations in gut microbiota and serum metabolic profiles were determined via 16S rRNA gene sequencing and untargeted metabolomics, respectively. Mechanistic insights were performed in NCM460 colonic epithelial cells through IDO1 silencing, ferroptosis inhibition, CETSA and molecular dynamics experiments. Furthermore, the synergistic and protective effects of HB on NDN were investigated in BLM-induced mice, along with analysis of intestinal microbiota composition. The active constituents of the EtOAc extract of Radix Pseudostellariae were identified using UPLC-Q-TOF-MS/MS, GNPS, and NMR spectroscopy. RESULTS:Administration of HB (40 mg/kg/day for approximately 14 days) significantly attenuated lung fibrosis progression and substantially alleviated diarrhea in BLM-induced PF mice. HB reshaped the intestinal microecology and reprogrammed serum metabolism, notably by reducing the abundance of Escherichia-Shigella, as revealed by 16S rRNA sequencing and untargeted metabolomics analyses. Furthermore, the co-treatment of HB and NDN demonstrated enhanced efficacy and reduced gastrointestinal toxicity both in vivo and in vitro. Mechanistic investigations indicated that HB-enriched 3-hydroxybutyric acid (3-HA) restored intestinal mucosal barrier integrity by inhibiting IDO1-mediated ferroptosis. Additionally, extracts of Radix Pseudostellariae containing HB-like cyclopeptides significantly improved PF symptoms and intestinal epithelial injury in BLM-induced mice. Nine cyclopeptide compounds (Herterophyllin A-B, D and Psedostellarin A-E, G) were identified in the extract via UPLC-Q-TOF-MS/MS analysis. CONCLUSION:HB offers dual protection against pulmonary fibrosis and intestinal damage through its regulatory impact on the gut-lung axis and suppression of ferroptosis mechanisms. Collectively, HB offers a promising adjuvant to optimize NDN-based antifibrotic therapy, offering a novel strategy for integrated pulmonary and gastrointestinal protection in PF management.

Long-term exposure to nanoplastics causes chronic toxicity in mammals, particularly in the gut and lung tissues. The gut-lung-microbiota axis plays a pivotal role in organisms through the management of gut bacteria amino acid metabolic homeostasis. However, chronic toxicity of nanoplastics from gut to lungs have yet to be fully elucidated. In this study, nanoplastics exposure not only causes colon inflammation but also results in lung fibrosis. The abundance of Akkermansia muciniphila (AKK) is decreased after nanoplastics exposure. Interestingly, a positive correlation is observed between AKK and indole-3-lactic (ILA). Supplementation with AKK or ILA ameliorated nanoplastics-induced gut-derived lung injury by restoring the balance of tryptophan metabolism. Furthermore, knocking down indoleamine 2,3-dioxygenase 1 (ido1) upregulated ILA levels, contributing to defense against damage from nanoplastics. These results suggest that regulating ido1 expression and AKK abundance, involved in tryptophan metabolic homeostasis (especially ILA production), maybe a strategy to reduce the biological toxicity induced by nanoplastics. Mogroside V, a natural product, is found to promote AKK growth and inhibit ido1, thereby ameliorating chronic toxicity induced by nanoplastics. The study offers a new understanding of how nanoplastics cause chronic toxicity by dysregulating gut-lung-microbiota axis, as well as strategies for preventing and treating nanoplastics.

Phospholipase A2 Group IIA (PLA2G2A), a secretory member of the phospholipase family, plays key roles in various physiological processes across multiple metabolic tissues. While PLA2G2A is expressed in lung epithelial cells and fibroblasts, its functions in lung injury and fibrosis remain poorly understood. In this study, we characterized the critical role of PLA2G2A in pulmonary fibrosis (PF) in both human patients and bleomycin (BLM)-induced PF mouse models. We found that PLA2G2A is significantly upregulated in the fibrotic lungs of both PF patients and mice, with its expression positively correlating with fibrotic gene markers. Functionally, PLA2G2A induced pyroptosis in lung epithelial cells, leading to mitochondrial damage, activation of the STING-NLRP3-GSDMD axis, and increased expression of α-SMA and COL1A1 in fibroblasts. Additionally, recombinant PLA2G2A protein directly induced the expression of IDO1 and α-SMA in human lung fibroblasts (HLFs) and primary mouse lung fibroblasts (MLFs). Mechanistically, PLA2G2A appears to alter lipid metabolism either directly or by activating IDO1, which exacerbates PF through AHRR-mediated inhibition of AHR. For therapeutic strategy, we administered Varespladib (a PLA2G2A inhibitor) and Indoximod (the selective IDO1 inhibitor) to the animals, both of which were found to mediate the progression of PF. Our findings suggest that PLA2G2A plays a central role in pro-fibrotic processes by modulating epithelial cells and fibroblasts, thereby promoting extracellular matrix production. Given its involvement in PF pathogenesis, PLA2G2A may serve as a potential therapeutic target for PF, with PLA2G2A inhibitors offering a promising strategy for clinical treatment.

ETHNOPHARMACOLOGICAL RELEVANCE:Wound healing is a complex biological process and remains a significant challenge due to the lack of effective therapeutic drugs. Cayratia japonica (CJG), a traditional folk medicine, has been widely used for its anti-inflammatory and efficacy in treating traumatic injuries. AIM OF THE STUDY:This study aimed to investigate the wound-healing effects of CJG and elucidate its underlying mechanism. METHODS:First, the phytochemical composition of CJG was identified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and its potential wound-healing mechanisms were predicated via network pharmacology. Next, in vivo experiments were conducted by dividing subjects into control, CJG (1.5-6 mg/cm2), and bFGF (150 IU/cm2) groups to assess its therapeutic efficacy. Finally, the mechanism of CJG and its key bioactive component, luteolin-7-O-glucoside (LUT-7G), were explained through polymerase chain reaction (PCR), Western blotting, histopathology, immunofluorescence, plasmid transfection, colony formation unit assays, and cellular thermal shift assay (CETSA). RESULTS:LC-MS/MS identified 15 major constituents of CJG and 102 potential wound healing-related targets. Network pharmacology analysis revealed key enriched pathways, including AMPK, TNF, and metabolic pathways. In vivo, CJG significantly accelerated wound-healing by inhibiting inflammatory responses, promoting angiogenesis, and modulating collagen deposition. In vitro, LUT-7G treatment markedly enhanced the proliferation and migration of HaCaT and HSF cells. Mechanistically, LUT-7G exerted its wound-healing effects by activating the AMPK/CTHRC1/TGF-β1 signaling pathway in HaCaT cells. In conclusion, CJG significantly promotes wound healing by regulating AMPK signaling pathways, indicating its promising clinical application prospects.

The pathogenesis of pulmonary fibrosis (PF) is complex. It is characterized by myofibroblast hyperplasia and deposition of collagen protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is expressed in lung fibroblasts and epithelial cells, but its functions in lung homeostasis and diseases remain elusive. Here, we characterize the critical role of IDO1 in PF patients and bleomycin (BLM)-induced PF mouse models. We find that IDO1 is significantly upregulated in the fibrotic lungs of patients and mice, showing a positive correlation with genes characteristic of fibrosis. Functionally, IDO1 knockout inhibits lung fibroblast proliferation, differentiation, mitochondrial biogenesis, and mitochondrial oxidative phosphorylation. Conversely, IDO1 overexpression and accumulation of kynurenine (Kyn) exacerbate progressive lung fibrosis. Mechanistically, IDO1-deletion activated profound mitochondrial fusion-enhanced potentially the capacity for fatty acid oxidation, along with activation of de novo glycolytic serine/glycine synthesis pathways and mitochondrial one-carbon metabolism. Wedelolactone (WEL), a small molecule IKK inhibitor, is found to strongly bind to IDO1 and effectively protect mice from PF in an IDO1-dependent manner. Collectively, this study characterizes a promotor role for IDO1 in PF and suggests a potential avenue of targeting IDO1 to treat lung diseases.

Acquired resistance is unavoidable in lung adenocarcinoma (LUAD) treated with osimertinib, however, the underlying mechanisms remain largely unknown. Here, we report that the long non-coding RNA (lncRNA) APCDD1L-AS1 is upregulated in osimertinib-resistant LUAD tissues and cells and is associated with short survival of osimertinib-resistant LUAD patients. Our data showed that APCDD1L-AS1 upregulation is an independent risk factor for overall survival in patients with osimertinib-resistant LUAD. APCDD1L-AS1 knockdown enhanced osimertinib sensitivity both in vitro and in vivo, whereas APCDD1L-AS1 overexpression promoted osimertinib resistance. Mechanistically, APCDD1L-AS1 accelerates the tricarboxylic acid (TCA) cycle by forming complexes and maintaining the stability of dihydrolipoamide S-succinyltransferase (DLST), which inhibits the ubiquitination and degradation of DLST. Moreover, we demonstrate that hypoxia-inducible factor (HIF)-1α transcriptionally activates APCDD1L-AS1 by binding to the APCDD1L-AS1 promoter region under hypoxic conditions. Overall, our data confirm that APCDD1L-AS1 is upregulated by hypoxia-induced HIF-1α, which drives the TCA cycle by stabilising DLST to further promote osimertinib resistance in LUAD. Our findings provide new insights into the role of HIF-1α/APCDD1L-AS1/DLST axis-related reprogramming of hypoxia and the TCA balance in conferring osimertinib resistance in LUAD and confirm the therapeutic potential for targeting the APCDD1L-AS1.

A key objective of forest tree breeding programs is to enhance traits related to growth and stem form, to cultivate plantations that exhibit rapid growth, straight trunks with minimal taper, and superior wood quality to meet the demands of modern timber production. Notably, Liriodendron species exhibit notable heterosis in interspecies hybrids, with hybrid Liriodendron displaying rapid growth rates, straight trunks, and wide adaptability. However, the genetic architecture underlying growth and stem form traits remains unclear, hindering the progress of genetic improvement efforts. Genome-wide association study (GWAS) emerges as an effective approach for identifying target genes and clarifying genetic architectures. In this study, a comprehensive analysis was conducted using an artificial population of 233 hybrid progeny derived from 25 hybrid combinations and resequenced to obtain genome-wide single nucleotide polymorphism (SNP) and insertion and deletion (InDel) variants. After filtering, a total of 192,972 SNP loci and 60,666 InDel loci were obtained, which were subsequently analyzed for associations using the R package GAPIT. We identified 97 significant SNP loci and 58 significant InDel loci (-Log10(P) ≥ 4.50), respectively, culminating in the identification of 161 candidate genes. The functions of these candidate genes were annotated, revealing potential associations between Lchi_2g03172 and Lchi_10g19986 genes with the growth of hybrid Liriodendron, and highlighting the potential influence of the Lchi_16g30522 gene on the growth and branching of hybrid Liriodendron. Overall, this study serves as a foundational step towards unraveling the genetic architecture underpinning growth and stem form in Liriodendron plants.

Recent years have witnessed significant advances in the development of novel techniques and methodologies for identifying active ingredients in traditional Chinese medicine (TCM), substantially advancing research and development efforts. Spectrum-effect correlation analysis, affinity ultrafiltration, high-content screening (HCS) imaging, and cell membrane chromatography (CMC) have emerged as essential tools, effectively linking TCM chemical constituents to their biological effects, thereby enabling efficient active ingredient screening. Additionally, molecular interaction analysis provides deeper insights into TCM-biomolecule interaction mechanisms, enhancing understanding of its therapeutic potential. Computer-aided techniques facilitate TCM active ingredient identification, optimizing the screening process for efficiency and cost-effectiveness. Molecular probe technology, as an emerging methodology, enables precise and rapid screening for novel therapeutic drug discovery. Ongoing technological advancement in this field indicates promising future developments, potentially leading to more effective and targeted TCM-based therapies.

Porcine epidemic diarrhea (PED) is a contagious intestinal disease caused by alpha-coronavirus porcine epidemic diarrhea virus (PEDV). At present, no effective vaccine is available to prevent the disease. Therefore, research for novel antivirals is important. This study aimed to identify the antiviral mechanism of Veratramine (VAM), which actively inhibits PEDV replication with a 50 % inhibitory concentration (IC50) of similar to 5 mu M. Upon VAM treatment, both PEDV-nucleocapsid (N) protein level and virus titer decreased significantly. The time-of-addition assay results showed that VAM could inhibit PEDV replication by blocking viral entry. Importantly, VAM could inhibit PEDV-induced phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) activity and further suppress micropinocytosis, which is required for PEDV entry. In addition, PI3K inhibitor LY294002 showed anti-PEDV activity by blocking viral entry as well. Taken together, VAM possessed anti-PEDV properties against the entry stage of PEDV by inhibiting the macropinocytosis pathway by suppressing the PI3K/Akt pathway. VAM could be considered as a lead compound for the development of anti-PEDV drugs and may be used during the viral entry stage of PEDV infection.