Acta Pharmaceutica Sinica B

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Potential oncogenic risks of Keap1-targeting PROTACs: Caution warranted in drug design

Acta Pharmaceutica Sinica B. 2026, 16(6): 3985-3987.
Opening endothelial gap while decompressing matrix: A coordinated mechanism enhancing drug delivery in pancreatic cancer treatment

Xiaochen Gu

Acta Pharmaceutica Sinica B. 2026, 16(6): 3988-3989.
Two receptors, one molecule: Reprogramming bile acid signaling for cardioprotection

Y. Eugene Chen

Acta Pharmaceutica Sinica B. 2026, 16(6): 3990-3991.
Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases

Acta Pharmaceutica Sinica B. 2026, 16(5): 2601-2644.

Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons—including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis—in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.
Cell-based regenerative interventions in Parkinson's disease: Overcoming pharmacological limitations

Ana Lizeth Padilla, José L. Lanciego, Miquel Vila, Fernando de Castro, David Pozo, Fernando Rodríguez de Fonseca, Antonia Serrano, Javier Sáez-Valero, Lucía Núñez, Carlos Villalobos, Victor Tapias

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

Mehrnaz Abbasi, Kai Sun, Kevin W. Huggins, Braeden Heath, Hannah DeLoit, Lauren McGinness, Kate Mccamy

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

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.
Mechanistic insights and therapeutic advances in antiviral strategies against African swine fever virus

Acta Pharmaceutica Sinica B. 2026, 16(5): 2730-2755.

African swine fever virus (ASFV) causes a highly contagious and lethal disease in domestic and wild pigs, posing a significant threat to global swine production. The lack of effective vaccines or antiviral therapies underscores the urgent need for alternative intervention strategies. In recent years, notable progress has been made in developing antiviral agents that target both viral components and host-dependent pathways. This review provides a comprehensive summary of recent advances in ASFV antiviral research, with a focus on therapeutic interventions aimed at viral-encoded proteins and host factors, particularly small-molecule inhibitors and their mechanisms of action. In addition, the review highlights target-agnostic and multifaceted antiviral strategies, including physical inactivation, early life cycle disruption, and gene-level interference, which act through broad or partially understood mechanisms. By integrating mechanistic insights with emerging therapeutic approaches, this review supports the rational design of antiviral interventions against ASFV and informs the subsequent exploration of candidate drugs with clinical translational potential.
Small molecules modulate the biomolecular condensates and liquid-liquid phase separation

Kaiyue Lian, Fajun Nan

Acta Pharmaceutica Sinica B. 2026, 16(5): 2756-2772.

Phase separation of biological macromolecules is a ubiquitous cellular mechanism for concentrating and compartmentalizing biochemical reactions. Emerging evidence reveals that biomolecular condensates formed via liquid-liquid phase separation (LLPS) play integral roles in diverse physiological processes, including gene expression and intracellular signaling, enabling rapid and delicate cellular responses. Dysregulation of phase separation is increasingly implicated in the pathogenesis of major diseases, ranging from neurodegenerative disorders and cancers to viral infections and aging. Consequently, deciphering the molecular mechanisms governing LLPS and developing strategies for its pharmacological modulation, particularly via small molecules, represent promising therapeutic targets offering novel approaches for disease intervention. In this review, we provide a concise overview of biomolecular condensates formation and their functions in diseases regulation. Mainly, we catalog commonly employed tool compounds, reported small-molecule modulators of LLPS, and related clinical progress within this rapidly evolving research area. Furthermore, we integrate recent technological breakthroughs in LLPS to envision the future trajectory and therapeutic potential of this field.
Nanotechnology-driven STING regulation for on-demand therapy

Qianwen Mu, Qihang Huang, Haolan Deng, Gang Liu, Chao Liu

Acta Pharmaceutica Sinica B. 2026, 16(5): 2773-2793.

The combination of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway modulation with nanotechnology offers a promising strategy for the development of more effective and less toxic therapies. This review summarizes the latest clinical progress of STING agonists and inhibitors, with a particular focus on the role of nanomaterials in regulating the cGAS-STING pathway across a range of diseases. In oncology, STING activation enhances anti-tumor immunity by stimulating immune cells, while nanocarriers improve the stability and targeting precision of STING agonists, facilitating synergistic effects with other immunotherapies. In inflammatory and autoimmune diseases, regulating STING activation helps alleviate the production of excessive pro-inflammatory cytokines, restore immune homeostasis, and prevent tissue damage. Nanomaterials, such as cell-derived membranes, further enhance targeted delivery and biocompatibility, addressing key limitations of existing treatment strategies. What distinguishes this review is an in-depth analysis of the current clinical progress of STING agonists and inhibitors, providing a comprehensive overview of both ongoing clinical trials and preclinical advancements. We also critically evaluate the specific challenges encountered in translating STING nanomaterials into clinical practice. These challenges present significant barriers to the widespread application of STING-based therapies, underscoring the need for further optimization to realize their full potential.

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