Asthma is a heterogeneous disease characterized by chronic airway inflammation and driven by diverse mechanisms, including T2-high, T2-low, and non-immune pathways. In traditional Chinese medicine(TCM), it is viewed as a syndrome of "root deficiency with branch excess", involving the dysfunction of the lung, spleen, and kidney. Animal models serve as crucial tools for investigating asthma mechanisms, screening therapeutic targets, and evaluating potential interventions, and their construction must closely align with disease pathogenesis. This study highlights a mechanism-guided approach to asthma animal modeling. It reviews models that reflect major immune phenotypes in modern medicine (T2-high, T2-low, and non-immune mechanisms)alongside TCM syndromes, including cold asthma, heat asthma, and kidney deficiency with phlegm retention. The construction principles, mechanistic links, and practical limitations of these models are analyzed. Emphasis is placed on optimizing models through a mechanism-oriented perspective and integrating Western and TCM frameworks. Such strategies are proposed to enhance the precision, translational value, and clinical relevance of asthma research using animal models.

Asthma is one of the most common chronic inflammatory airway diseases worldwide. Although current treatments can control symptoms, they are unable to fundamentally regulate the underlying immunopathological processes. Xiao'er Jiangqi Pingxiao Mixture (JPM) is a clinically used empirical prescription for the treatment of asthma. Previous studies have confirmed its efficacy in improving asthma symptoms, but its underlying mechanism remains to be elucidated. In this study, transcriptomic data from nasal brush samples of pediatric asthma patients (GSE152004) and lung tissue transcriptomic data from asthmatic mice (GSE41665) were integrated. Core targets were identified using machine learning, and their association with the immune microenvironment of asthma was explored through immune cell infiltration analysis. Pharmacodynamic evaluation and mechanistic validation were then performed in an ovalbumin (OVA) -induced asthma mouse model. The pharmacodynamic results showed that JPM significantly reduced the levels of interleukin (IL) -4 and IL-5 in bronchoalveolar lavage fluid (BALF) of model mice and alleviated airway inflammatory infiltration, mucus secretion, and collagen deposition. Machine learning identified seven core genes, among which IL-13 and interleukin-1 receptor-like 1 (IL-1RL1) were significantly positively correlated and closely associated with the infiltration of pro-inflammatory immune cells such as activated dendritic cells and type 1 macrophage (M1).Enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and real-time quantitative PCR (RTqPCR) further demonstrated that JPM significantly downregulated the protein expressions of IL-13 and IL-1RL1 in BALF, suppressed the positive expressions of complement C1q subcomponent subunit A (C1QA) and subunit C (C1QC) in lung tissues, and reduced the messenger RNA (mRNA) levels of IL-33, thymic stromal lymphopoietin (TSLP), and the complement receptor low-density lipoprotein receptor-related protein 1 (LRP1). Collectively, these findings suggest that JPM may ameliorate the experimental asthma phenotype by interfering with the "epithelial alarmin-complement-mediated presentation-type 2 immune amplification" cascade axis (specifically through inhibiting IL-33/TSLP release, blocking C1QA/C1QC-LRP1 mediated antigen presentation, and modulating the IL-1RL1/IL-13 axis), thereby systematically restoring the helper T cell 2 (Th2) immune microenvironment homeostasis. This study provides an experimental basis for further mechanistic investigation and clinical application of JPM. All animal experiments were approved by the Animal Ethics Committee of China Academy of Chinese Medical Sciences (approval No.: 2026B039).

The study aims to investigate the potential active ingredients and mechanism of action of XKZ2305 Granules in treating pediatric cough and asthma syndrome. An HPLC-Q-TOF-MS/MS method was established to rapidly identify the chemical constituents in XKZ2305 Granules using electrospray ionization (ESI) source in both positive and negative ion scanning modes. A total of 174 compounds were identified, including 46 flavonoids, 30 terpenoids, 16 alkaloids, 18 phenolic acids, and 64 other components. Integrated with network pharmacology analysis, potential targets of these chemical components and asthma-related disease targets were retrieved from the TCMSP, Swiss Target Prediction, GeneCards, and OMIM databases, respectively. After screening, 451 overlapping targets were obtained. Protein-protein interaction (PPI) analysis was performed using the STRING database, and visualization of the PPI network and the "herb-compound-target" network was conducted using Cytoscape software, leading to the identification of 29 core targets. GO (gene ontology) functional enrichment and KEGG (Kyoto encyclopedia of genes and genomes) pathway analyses via the DAVID database revealed that the therapeutic mechanism of XKZ2305 Granules against pediatric cough and asthma syndrome components, including baicalein, wogonin, quercetin, sinapine thiocyanate, and rhynchophylline, act on targets such as TP53, IL6, IL1B, HIF1A, GAPDH, BCL2, and AKT1, primarily through the HIF-1, PI3K/AKT, AGE-RAGE, and MAPK signaling pathway. Animal experiments demonstrated that XKZ2305 Granules significantly improved behavioral changes in juvenile asthmatic mice induced by ovalbumin (OVA), markedly reduced serum IgE levels and TNF-α content in bronchoalveolar lavage fluid (BALF), showed a trend toward increasing IL-10 levels, alleviated OVAinduced airway inflammation, and consequently mitigated pediatric asthma and cough syndrome. This study comprehensively identified the chemical constituents of XKZ2305 Granules. The animal experiments involved in this study have been approved by the Institutional Animal Care and Use Committee of Tianjin Institute of Pharmaceutical Research (Approval No.: TIPR-2025-2361PD9).

To characterize the material basis of Jiangqi Pingxiao Formula (JQPXF), this study employed feature-based molecular networking (FBMN), identifying a total of 237 chemical components. Based on FBMN, we further compared the chemical profiles of clinical Pediatric Jiangqi Pingxiao Mixture (HJ) and water decoction mixture (JJ) via non-targeted HRMS. The results revealed distinct chemical signatures in iridoids and terpenoids for the mixture, while the decoction showed preferential extraction of glycosides. Notably, in vivo exposure studies demonstrated that 24 components exhibited high pulmonary distribution, suggesting their potential as the direct material basis. Concurrently, 48 components showed delayed exposure in colonic contents, suggesting a potential effect for modulating gut microbiota against asthma through lung-gut axis. Further mechanistic analysis revealed a total of 11 core targets. Beyond classical anti-inflammatory pathways (e. g., TNF signaling), the formula may intervene in oxidative stress and airway remodeling through multiple mechanisms, including the inhibition of programmed cell death, modulation of 14-3-3 protein signaling, and regulation of lipid metabolism and fluid shear stress. This study comprehensively elucidates the "multi-component and multi-pathway" characteristics of JQPXF, providing a scientific foundation for its clinical application and formulation optimization (All animal experiments in this study were approved by the Animal Experimental Ethics Committee of Nanjing University of Chinese Medicine, Ethics No.: 202210A028).

Phenotypic drug discovery (PDD) represents a vital source of first-in-class drug innovation; however, its central bottleneck — demonstrating efficacy without a clear mechanism of action — remains a fundamental challenge in modern medicinal chemistry. This review discusses how chemical biology serves as a critical link between phenotypic screening and target validation, leveraging an integrated technological repertoire — including chemical proteomics, genetically encoded biosensors, and chemical genetics — to seamlessly connect phenotypic assays with target deconvolution, thereby accelerating the iterative cycle of "phenotypic investigation → target identification → medicinal chemistry optimization". Drawing upon cutting-edge modalities such as proteolysis targeting chimera (PROTACs) and molecular glues, we analyze the pivotal role of chemical biology in lead discovery, target deconvolution, mechanistic elucidation, and the design of novel drug modalities. Looking forward, the field is poised to deeply integrate artificial intelligence (AI)-driven drug design and single-cell chemical genomics to tackle previously undruggable targets and drive the modern revival of natural products. Concurrently, its research paradigm is shifting from a narrow focus on molecular mechanisms toward a systems-level regulation of biological networks, ultimately laying a solid technological foundation for precision medicine and the development of next-generation therapeutic modalities.

Pancreatic cancer is one of the digestive system malignancies with the poorest prognosis, with a five-year survival rate of only approximately 13%, and even lower at 8.5% in the Chinese population. Due to difficulties in early diagnosis, most patients are already at an advanced stage at the time of diagnosis, with limited treatment options and a propensity for resistance to radiotherapy and chemotherapy. KRAS (kirsten rat sarcoma viral oncogene homolog) mutations occur in over 90% of pancreatic cancer cases. Mutant KRAS not only drives tumor proliferation but also remodels the immune microenvironment through various mechanisms, such as inducing infiltration of immunosuppressive cells and upregulating immune checkpoint molecules, thereby leading to immune evasion. In recent years, with the introduction of KRAS inhibitors into clinical practice, targeting KRAS has shown potential for remodeling the tumor immune microenvironment. This article systematically reviews the mechanisms by which KRAS mutations contribute to the formation of an immunosuppressive microenvironment in pancreatic cancer, the progress in the development of KRAS-targeted drugs, and the current status and challenges of their combination with immunotherapy, providing new insights for precision treatment of pancreatic cancer.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most prevalent chronic liver disease worldwide. Its pathogenesis involves the interplay of lipid dysregulation, insulin resistance, oxidative stress, inflammation, gut microbiota dysbiosis, and genetic susceptibility variants. Current therapeutic interventions primarily rely on systemic administration, with their hepatic specificity or selectivity remaining to be improved. Small interfering RNA (siRNA) therapy offers a novel strategy by precisely silencing hepatic pathogenic genes to block aberrant protein synthesis. This review outlines the mechanisms of action and the delivery systems of siRNA therapeutics. Focusing on the core pathological drivers of MASLD, it details the clinical progress and mechanistic insights of siRNA therapeutics within three main areas: Genetic risk variants, lipid metabolism regulation, and fibrosis-inflammation pathways. This article provides an updated reference for siRNA drug development in MASLD.

Colorectal cancer (CRC) is a highly prevalent malignant tumor of the digestive system worldwide, and resistance to chemotherapy and immunotherapy constitutes a major challenge in its clinical management. While lipid metabolic reprogramming supports tumor proliferation, it also confers a specific metabolic susceptibility of CRC cells to ferroptosis, an iron-dependent form of programmed cell death driven by the accumulation of lipid peroxides. CRC cells promote the membrane incorporation of polyunsaturated fatty acids (PUFAs) by upregulating acyl-CoA synthetase long-chain family member 4 (ACSL4), reduce membrane lipid unsaturation by activating stearoyl-CoA desaturase 1 (SCD1), and rely on the solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) antioxidant system, together with parallel pathways such as ferroptosis suppressor protein 1 (FSP1) and dihydroorotate dehydrogenase (DHODH), to eliminate peroxides and maintain the dynamic balance of the "lipid-ferroptosis axis". Owing to their multi-target regulatory advantages, natural bioactive compounds specifically intervene in this axis by inhibiting fatty acid desaturation, inducing lipophagic substrate mobilization, blocking antioxidant defenses, and disrupting iron homeostasis, thereby triggering ferroptosis in CRC cells. In addition, the combination of natural products with chemotherapeutic agents or immune checkpoint inhibitors can effectively reverse metabolism-adaptive resistance and activate antitumor immunity by inducing immunogenic ferroptosis. Given that clinical translation still faces challenges such as poor druggability and the lack of predictive models for therapeutic efficacy, the authors systematically analyzed the pharmacodynamic material basis and molecular mechanisms by which natural bioactive compounds modulate the lipid-ferroptosis axis, with the aim of providing a theoretical foundation for the development of drugs targeting metabolic remodeling and for the optimization of combination therapeutic strategies.

With the discovery that thalidomide-like drugs induce the ubiquitination and degradation of target effector proteins, drug development based on similar mechanisms, such as proteolysis targeting chimera (PROTAC), has rapidly expanded worldwide, occupying a considerable proportion of the novel drug discovery landscape. As the first clearly identified effector proteins of thalidomide-like drugs, the Ikaros family has also garnered broader attention. Although recent research on this family continues to focus on the development and differentiation of immune cells, a particular shift in interest has been observed toward regulatory T cells (Tregs). Correspondingly, thalidomide-like drugs are now being explored for use in autoimmune diseases, such as systemic lupus erythematosus. As transcription factors, the regulatory mechanisms of Ikaros family proteins have long been a research hotspot. Among various findings, the role of Ikaros in organizing genomic spatial architecture stands out as particularly prominent. Here, we first briefly review the research progress on thalidomide-like drugs, and then summarize newly discovered physiological functions and molecular regulatory mechanisms of Ikaros family proteins. By organizing and analyzing this information, we aim to clarify trends in related research and explore potential strategies for further targeting the Ikaros protein family.

Maintaining intracellular purine nucleotide homeostasis is critical for sustaining normal cellular physiology. Inosine-5′-monophosphate dehydrogenase (IMPDH) acts as the rate-limiting enzyme in the de novo purine nucleotide biosynthesis (DNPNB) pathway, directly regulating intracellular guanine nucleotide synthesis levels. In rapidly proliferating tumor cells, IMPDH is aberrantly activated to meet heightened nucleic acid demands, rendering it a promising target for cancer therapy. Despite the advancement of several candidates — including tiazofurin — into clinical trials, no IMPDH-targeted antitumor drugs have been approved for marketing, highlighting the need for more rigorous and systematic investigation in this field. This review summarizes the structural and functional properties of IMPDH and the progress in developing IMPDH-targeting anticancer drugs, with the aim of providing insights for future research.