Acta Pharmaceutica Sinica B

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.

Advances in GLP-1 receptor agonists delivery systems for obesity and diabetes

Acta Pharmaceutica Sinica B. 2026, 16(5): 2682-2710.

Obesity and diabetes are chronic metabolic diseases affecting millions worldwide. Current treatments, including lifestyle changes, medications, and surgery, face challenges like poor adherence and side effects. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended innovative medications for these conditions, with studies showing significant clinical benefits. GLP-1RAs are traditionally delivered orally or via subcutaneous injections, but these methods have limitations, including low bioavailability, poor solubility, the need for high doses, gastrointestinal side effects, and frequent dosing requirements. Novel delivery technologies offer promising strategies to overcome these challenges and enhance therapeutic effectiveness. Recent advances in drug delivery technologies, including nanocarrier- and microcarrier-based systems, hydrogels, microneedles, and innovative formulations such as long-acting, co- and/or nano-formulated agents, offer promising strategies to enhance the delivery, efficacy, and patient adherence of GLP-1RAs for obesity and diabetes. This review focuses on innovative delivery technologies developed for three main GLP-1RAs: exenatide, liraglutide, and semaglutide. We present a review of advancements in drug delivery systems, exploring technologies employed in the development of these agents, as well as future challenges. It is crucial to note that these technologies are still in early development, and further studies are needed to confirm their long-term safety, efficacy, and cost-effectiveness in clinical use.

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.

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.

Exploring specialized metabolic pathways in medicinal plants with single-cell and spatial omics

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.

Cell-based regenerative interventions in Parkinson's disease: Overcoming pharmacological limitations

Acta Pharmaceutica Sinica B. 2026, 16(5): 2645-2681.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and the pathological aggregation of α-synuclein. While current pharmacological therapies provide symptomatic relief, they do not halt or reverse disease progression. Cell-based regenerative strategies have emerged as promising approaches to restore DA function and target the complex, multifactorial pathophysiology of PD. This review critically examines current approaches, including transplantation of fetal ventral mesencephalic tissue, pluripotent stem cell-derived midbrain DA progenitors, and in vivo reprogramming of endogenous cells. In addition, supportive cell types, such as mesenchymal stromal cells and carotid body glomus cells, provide neuroprotective and immunomodulatory effects via paracrine signaling. We summarize preclinical and clinical evidence on graft survival, integration, and functional recovery, and discuss key determinants of therapeutic efficacy, including mitochondrial function and bioenergetic integrity, immune compatibility, and biomaterial scaffolding. Despite significant progress, major challenges remain regarding long-term efficacy, graft standardization, and host-graft interactions. Ongoing translational advances are poised to drive the development of disease-modifying cell therapies capable of delivering durable clinical benefits and improving long-term outcomes in PD.

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.

DeepICER: A deep learning framework for predicting compound-induced gene expression profiles

Fanbo Meng, Can Wang, Yue Lin, Jing Mo, Xunzhi Zhang, Zhaotong Cong, Chi Song, Sanyin Zhang, Shilin Chen, Liang Leng, Wei Chen

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.

Interactions between the gut microbiome and ferroptosis in degenerative diseases: Novel mechanisms and potential therapeutic strategies

Yue Chen, Xiang Wei, Xin Yi, Ding-Sheng Jiang

Acta Pharmaceutica Sinica B. 2026, 16(5): 2711-2729.

Degenerative diseases are a group of medical conditions characterized by the progressive and irreversible deterioration of cells, tissues, and organs over time. Emerging evidence highlights the alteration and functions of the gut microbiome in the development of degenerative diseases. Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, has been implicated as a pivotal factor in the regulatory effect of the gut microbiome on degenerative diseases. Moreover, gut metabolites, particularly short-chain fatty acids and trimethylamine N-oxide, are closely related to iron overload, redox imbalance, and lipid peroxidation. Recently, microbiome-based therapies, such as fecal microbiota transplantation, have been considered novel therapeutic strategies. In this review, we focus on degenerative diseases and explore the interactions between the gut microbiome and ferroptosis, aiming to provide new insights into the underlying mechanisms and clinical implications.

Ferroptosis-based nano-assembly enhanced breast cancer therapy by inhibiting intratumor bacteria

Acta Pharmaceutica Sinica B. 2026, 16(3): 1733-1746.

Intratumoral bacteria, especially Gram-positive bacteria (G⁺), have a unique bacterial niche in breast cancer that promoted tumor progression. However, the effects of G⁺ have so far been overlooked, serving an “invisible driver” of breast cancer. Moreover, due to the altered biological structure of G⁺ in tumor cells and the penetration barrier of antibiotics, the effect of antibiotic-mediated eradication of G⁺ in tumors is limited. Here, to simultaneously inhibit intratumoral G⁺ and tumor cells via ferroptosis therapy, an amorphous nano-assembly (DFTV) was constructed by assembling doxorubicin (DOX), tannic acid (TA), FeSO₄, and vancomycin (Van). DFTV treatment effectively targets intratumoral G⁺, thereby inhibiting the growth of the breast tumor and postoperative recurrence by downregulating the expression of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α). Moreover, inhibiting intracellular G⁺ also restrains the reorganization of F-actin to form pseudopodia, thereby impairing tumor cell motility and blocking metastasis. Collectively, DFTV improves the antitumor efficacy by targeting G⁺ in breast tumors, offering novel insights into overcoming the limitations associated with the lack of intratumoral antibacterial therapy in clinical breast cancer treatment protocols.