Acta Pharmaceutica Sinica B

Home Latest Articles

Latest Articles

Advances in immune cell-based therapeutic agents for the treatment of inflammation-related diseases

Yuxin Yang, Jinhu Liu, Jie Liu, Suyun Wei, Xiaohui Kong, Weiwei Mu, Yongjun Liu, Na Zhang

Acta Pharmaceutica Sinica B. 2026, 16(5): 2794-2837.

Inflammation-related diseases account for over 50% of global disease-associated mortality; the core pathological mechanisms of these diseases are closely linked to functional dysregulation of immune cells such as macrophages and T cells. Aberrantly activated immune cells excessively secrete inflammatory mediators, which drive chronic inflammatory cascades and trigger irreversible tissue damage. In recent years, immune cell-based therapeutic agents (ICTAs) have garnered significant attention due to their inherent targeting specificity and immunomodulatory capabilities, encompassing whole immune cells, cell membranes, or extracellular vesicles serving as active therapeutics or delivery carriers. This review systematically elaborates on strategies for constructing ICTAs through nanoengineering, genetic engineering, and membrane-fused engineering, while outlining their integrating applications with other delivery devices. Furthermore, we summarize the preclinical and clinical trial advancements of ICTAs in various diseases such as tumors, rheumatoid arthritis, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, ischemia/reperfusion injury, sepsis, and hemophagocytic lymphohistiocytosis. These insights establish an interdisciplinary design framework for developing clinically applicable ICTAs and propose novel therapeutic approaches for inflammation-related diseases.
Extracellular vesicles: Revolutionizing targeted therapy for ischemic stroke

Acta Pharmaceutica Sinica B. 2026, 16(5): 2838-2876.

Ischemic stroke (IS) remains a leading cause of global death and disability, with treatment effectiveness limited by its complex mechanisms, which include blood-brain barrier (BBB) disruption, neuroinflammation, excitotoxicity, oxidative stress, and cell death. This review summarizes emerging research on extracellular vesicle (EV)-based therapies for IS. EVs, sourced from animals, plants, and microbes, have unique benefits as natural nanocarriers, such as inherent BBB permeability, biocompatibility, and the ability to deliver multiple therapeutic cargos (like miRNAs, proteins, and drugs). We evaluate how EVs target key IS issues: (1) restoring BBB integrity by stabilizing tight junctions (TJs) and reducing matrix metalloproteinases (MMPs), (2) modulating microglia to reduce neuroinflammation, (3) decreasing excitotoxicity, (4) scavenging reactive oxygen species (ROS) to lessen oxidative stress, and (5) inhibiting apoptosis, ferroptosis, and other cell death pathways. Additionally, engineered EVs, such as antibody-conjugated or magnetically guided types, exhibit improved targeting and treatment accuracy, yielding promising results. Despite significant preclinical promise, clinical application faces challenges in standardization, scalable production, and delivery improvement. EVs offer a transformative, multi-targeted approach with the potential to overcome current limitations in IS treatment.
Analysis of intratumoural bacteria: Opportunities and challenges for cancer therapy

Acta Pharmaceutica Sinica B. 2026, 16(5): 2877-2902.

Intratumoural bacteria have been shown to play conflicting roles within tumours, especially in the modulation of immune responses. Moreover, bacteria have been linked to a variety of cancer types and have different prognostic values depending on the cancer. This heterogeneity is not only shaped by tumour molecular subtypes, spatial location, cancer progression stage, genetic alterations, and the presence of multiple subclones, but is also influenced by variations in angiogenesis, oxygen levels, microbial sources, endocytosis and micropinocytosis. In this review, we describe the diversity of intratumoural bacteria across 25 cancer types covering an extensive spectrum of analyzed intratumoural bacteria. Furthermore, the dual roles and mechanisms of their involvement in tumour progression and anticancer activity are summarized. Additionally, interventions and applications of engineered bacteria in cancer therapy, especially strategies used in clinical trials, are illustrated. This work describes the roles of intratumoural bacteria and their metabolic byproducts as regulators within the tumour microenvironment and highlights the potential translation of bacteria for cancer therapy.
Non-viral delivery of genome-editing tools for treatment of genetic disorders

Acta Pharmaceutica Sinica B. 2026, 16(5): 2903-2928.

Pathogenic mutations within protein-coding regions of genomic DNA can disrupt protein structure and lead to hereditary disorders. Genome-editing technologies, particularly those based on clustered, regularly interspaced, short palindromic repeats-associated protein (CRISPR-Cas), are promising therapeutic tools for correcting genetic abnormalities. To date, viral delivery vectors for genome-editing biomacromolecules have shown numerous promises in treating genetic disorders. However, safe viral delivery for genome-editing components remains challenging, largely due to the immunogenicity of viruses. As an alternative, non-viral delivery systems are emerging as a safer choice and may offer solutions to address the safety challenges. In this review, we first introduce CRISPR-Cas9-based genome editing tools and their delivery formats. Then, we outline the pathology of major genetic disorders and both preclinical and clinical approaches for these diseases by therapeutic genome editing, and provide an overview of current non-viral delivery strategies and their potential to overcome existing limitations. Finally, we discuss the current challenges and future outlooks of non-viral delivery of gene-editing components in treating genetic diseases.
Exploring specialized metabolic pathways in medicinal plants with single-cell and spatial omics

Guo Li, Miaomiao Cai, Xinhao Liao, Guang-Lei Ma, Xiaohui Fan

Acta Pharmaceutica Sinica B. 2026, 16(5): 2929-2946.

Medicinal plants synthesize an immense diversity of specialized metabolites that play crucial roles in ecological interactions and serve as valuable pharmaceutical resources. However, the biosynthetic pathways responsible for this chemical diversity remain largely uncharacterized. These pathways are often complex, involving multiple steps that are spatially and temporally orchestrated within highly specialized or rare cell types. Classical bulk omics approaches obscure such cellular heterogeneity by averaging signals across tissues, limiting their utility in resolving cell-specific metabolic processes. Recent advances in single-cell and spatial omics technologies have revolutionized the ability to investigate plant metabolism at high spatiotemporal resolution, as exemplified by monoterpene indole alkaloids and Taxol biosynthesis. In this review, we highlight key technological advances in plant single-cell and spatial omics, examine their applications in pathway discovery and partitioning, and discuss emerging directions for harnessing these tools in plant synthetic biology and metabolic engineering. These developments promise to accelerate the systemic mapping of plant metabolic networks and facilitate their biotechnological exploitation for pharmaceutical development.
DeepICER: A deep learning framework for predicting compound-induced gene expression profiles

Acta Pharmaceutica Sinica B. 2026, 16(5): 2947-2963.

Accurate prediction of drug-induced gene expression profiles is crucial for phenotype-based drug discovery. Although computational methods have shown potential, they struggle with the complexities of varying doses and durations. To overcome these limitations, we developed DeepICER, a model that predicts gene expression profiles induced by chemical perturbations across any dose and duration. Utilizing a bilinear attention mechanism, DeepICER captures the interplay between dose, duration, and basal gene expression, enabling accurate predictions for novel compounds and cell lines. DeepICER outperforms existing models with superior flexibility in handling any dose and duration and accuracy, achieving a 45.1% improvement in predictive performance. Experimental validation confirmed that PD-166285, identified by DeepICER, exhibits stronger inhibitory effects on A549 cells compared to paclitaxel. To enhance accessibility, DeepICER is developed as an online platform, providing researchers with a tool to predict gene expression in compound-treated cells, thereby advancing drug repurposing and accelerating drug discovery.
Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease

Acta Pharmaceutica Sinica B. 2026, 16(5): 2964-2981.

Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors can reduce seizures in temporal lobe epilepsy (TLE) by upregulating excitatory amino acid transporter 2 (EAAT2, also known as GLT-1). While the Hsp90 inhibitor 17-AAG is effective, its long-term use raises toxicity concerns. This study aimed to identify a safer Hsp90 inhibitor by screening benzenoid ansamycin derivatives for higher binding affinity and lower toxicity. Among nine natural benzenoid ansamycins and their derivatives screened, reblastatin emerged as the top candidate, exhibiting the highest binding affinity to Hsp90. Compared to geldanamycin and 17-AAG, reblastatin demonstrated significantly lower cytotoxicity in HEK293 and HepG2 cells. Like 17-AAG, reblastatin upregulated EAAT2 levels by disrupting the association among Hsp90, EAAT2, and the 20S proteasome. In a kainic acid-induced TLE mouse model, reblastatin reduced seizure frequency by 50%, with long-term treatment showing toxicity comparable to vehicle controls. Additionally, behavioral tests revealed neuroprotective effects of reblastatin in mouse models of Alzheimer's disease and Parkinson's disease. These findings collectively suggest that reblastatin is a promising Hsp90 inhibitor for treating TLE and excitotoxic conditions associated with neurodegenerative diseases.
CD74 deficiency protects against doxorubicin cardiotoxicity through RRM2-mediated regulation of ferroptosis

Acta Pharmaceutica Sinica B. 2026, 16(5): 2982-3000.

Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major health threat that limits its clinical application. While mitochondrial dysfunction, oxidative stress and ferroptosis are implicated in DIC pathology, the precise mechanism remains elusive. This study evaluated the role of cluster of differentiation 74 (CD74), an immunoregulatory protein, in DIC. Our findings revealed elevated CD74 levels in blood samples from DOX-exposed patients and DOX-challenged mouse hearts. CD74 deletion mitigated DOX-indued cardiac remodeling, contractile anomaly, mitochondrial abnormalities, apoptosis, and ferroptosis. Mechanistically, CD74 bound to DNA synthesis molecule ribonucleotide reductase M2 (RRM2), redistributing it from cytoplasm to plasma membrane, impairing DOX-induced repair and exacerbating mitochondrial injury, apoptosis, and ferroptosis via activation of RRM2/p53 cascade. Notably, a CD74 mutant (aa 220-250) failed to aggravate DOX-induced cardiac dysfunction, unlike WT CD74. Moreover, the protective effects of CD74 inhibition in cardiomyocytes were negated by p53 activation, highlighting its role in DOX-induced damage. Treatment with CD74 inhibitor Amifostine in a DIC mouse model significantly alleviated cardiac remodeling and functional impairment by reducing oxidative stress and ferroptosis. Transwell study using the CD74-null Raw 264.7 macrophages and cardiomyocytes revealed that CD74 knockdown in macrophages overly attenuated DOX-instigated cardiomyocyte dysfunction. These findings establish CD74 as a potential therapeutic target for DIC, as its regulation of RRM2 cytomembrane diversion and ferroptosis ultimately drives cardiac remodeling and contractile anomalies in response to DOX challenge.
Oridonin as a novel KDM5C inhibitor alleviates clonal hematopoiesis-induced cardiac aging via H3K4me3-dependent SASP suppression

Acta Pharmaceutica Sinica B. 2026, 16(5): 3001-3025.

TET2-mediated clonal hematopoiesis of indeterminate potential (CHIP) is a known cardiovascular risk factor, but its role in cardiac aging and potential for pharmacological intervention remain unclear. Herein, Mendelian randomization using large-scale genome-wide association studies (GWAS) data assessed CHIP's causal impact on aging and cardiovascular disease that revealed significant causal associations between TET2-CHIP, CVD, and aging biomarkers. Transcriptome-guided screening identified oridonin as a candidate compound reversing CHIP- and aging-associated gene signatures. Multi-tiered target prediction combining chemical structure-based algorithms and transcriptomic correlation identified KDM5C as a key target, validated by enzymatic inhibition and surface plasmon resonance assays. In vivo and in vitro administration of oridonin significantly ameliorated cardiac dysfunction and pathological remodeling in the CHIP model. Epigenetic regulation was profiled via ChIP-seq and RNA-seq, focusing on H3K4me3-mediated transcription. Tet2⁺/⁻BMT mice exhibited age-progressive myocardial fibrosis, inflammation, senescence, and functional decline. Mechanistically, oridonin inhibited KDM5C histone demethylase, restored H3K4me3 levels, and activated the SIRT2 anti-aging pathway. Rescue experiments using gene overexpression and recombinant protein supplementation confirmed the functional role of the KDM5C-H3K4me3-SIRT2-S100A8 axis in mediating oridonin's effects. Overall, TET2-driven CHIP promotes cardiac aging, as evidenced by human genetic analyses and long-term BMT models. Oridonin, by inhibiting KDM5C and restoring H3K4me3-dependent SIRT2 signaling, mitigates CHIP-induced myocardial aging.
Curcumin ameliorates metabolic dysfunction-associated steatotic liver disease via targeting triokinase/FMN cyclase to regulate the expression of glycerol-3-phosphate acyltransferase 3: Integration of chemical proteomics and transcriptomics

Acta Pharmaceutica Sinica B. 2026, 16(5): 3026-3042.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, posing public health risks from potential irreversible liver damage. Curcumin (Cur), a polyphenolic compound from Zingiberaceae and Araceae, exhibits antihyperlipidemic and insulin-sensitizing effects. However, its targets and mechanisms in MASLD remain unclear. This study aimed to identify the potential targets and mechanisms by which Cur ameliorates MASLD. Cur markedly improved metabolic disorders and inflammation in rats and reduced intracellular lipid accumulation in HepG2 cells, primary hepatocytes, and AML12 cells. TKFC was identified as a direct target of Cur which binds to TKFC at Val136 and Glu538, thereby activating it. Gene microarray screening showed that Cur down-regulated the mRNA expression of Gpat3. TKFC knockdown attenuated the down-regulation of GPAT3 by Cur, whereas TKFC overexpression reversed this effect. In Tkfc-deficient mice, the therapeutic effects of Cur were attenuated and the down-regulation of GPAT3 and related proteins was hindered, thereby promoting triglyceride production in the liver. Further mechanistic studies revealed that Cur targets TKFC to inhibit GPAT3 expression by modulating the AMPK-STAT3 axis. Our study highlights TKFC as a novel and promising target for MASLD and offers new insights into the molecular mechanisms through which Cur ameliorates MASLD.

Previous 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 Next

Submission

Peer Review

Staff Login