Acta Pharmaceutica Sinica B

Deciphering the significant impact of natural glycosylation on human insulin

Acta Pharmaceutica Sinica B. 2025, 15(11): 5880-5890.

In the century-long evolution of insulin pharmaceuticals, each transformative advancement in this drug class has been closely tied to the ability to obtain new insulin isoforms for research. Despite this, the recently discovered naturally occurring isoforms of glycosylated human insulin have remained largely unattainable for proper characterization. Herein, we demonstrate for the first time that total chemical synthesis can be used to generate all isoforms. This achievement required maintaining the correct positions of the interchain disulfide bonds while effectively removing protecting groups on complex glycans. Notably, the availability of seven glycoforms reveals the important effects of natural sialylated glycans in suppressing insulin self-association and enhancing its solubility, surpassing the performance of currently employed rapid-acting insulin drugs. This work not only offers a readily adaptable platform for exploring natural O-glycosylation in other therapeutic proteins and peptides but also lays the groundwork for further research into harnessing natural glycosylation for therapeutic applications.

Next-generation clinically relevant antibody detection: Unlocking electrochemical biosensors for critical disease management

Zheng Zhao, Zhiwei Chen, Jacques Crommen, Shengfeng Huang, Qiqin Wang, Zhengjin Jiang

Acta Pharmaceutica Sinica B. 2025, 15(11): 5632-5662.

Autoimmune diseases, cancers, and viral infections pose significant global health threats, characterized by chronic pathology, unregulated cellular proliferation, and rapid transmission, respectively, requiring urgent early warning and treatment strategies. Antibodies, primarily classified into autoantibodies and therapeutic antibodies based on their clinical roles, provide essential information and show considerable value in the precise diagnosis and treatment of these serious diseases. Among the technologies utilized in bioanalysis, electrochemical biosensors, with their unique advantages of rapid response, high sensitivity, miniaturization, cost-effectiveness and user-friendly operation, have been developed as a trending technology for precise diagnostic and therapeutic drug monitoring. This review systematically summarizes the relationships and roles of clinically relevant antibodies in autoimmune diseases, cancers, and viral infections, while detailing the composition, strategies, development, and application trends of relevant electrochemical biosensors. Furthermore, it highlights the remaining challenges and opportunities for the advancement and prospects of electrochemical sensors in the context of clinically relevant antibodies.

Application of artificial intelligence in laboratory hematology: Advances, challenges, and prospects

Hongyan Liao, Feng Zhang, Fengyu Chen, Yifei Li, Yanrui Sun, Darcée D. Sloboda, Qin Zheng, Binwu Ying, Tony Hu

Acta Pharmaceutica Sinica B. 2025, 15(11): 5702-5733.

The diagnosis of hematological disorders is currently established from the combined results of different tests, including those assessing morphology (M), immunophenotype (I), cytogenetics (C), and molecular biology (M) (collectively known as the MICM classification). In this workflow, most of the results are interpreted manually (i.e., by a human, without automation), which is expertise-dependent, labor-intensive, time-consuming, and with inherent interobserver variability. Also, with advances in instruments and technologies, the data is gaining higher dimensionality and throughput, making additional challenges for manual analysis. Recently, artificial intelligence (AI) has emerged as a promising tool in clinical hematology to ensure timely diagnosis, precise risk stratification, and treatment success. In this review, we summarize the current advances, limitations, and challenges of AI models and raise potential strategies for improving their performance in each sector of the MICM pipeline. Finally, we share perspectives, highlight future directions, and call for extensive interdisciplinary cooperation to perfect AI with wise human-level strategies and promote its integration into the clinical workflow.

Brain endothelial HIF-1α exacerbates diabetes-associated cognitive impairment by accelerating glycolysis-driven lactate production

Acta Pharmaceutica Sinica B. 2025, 15(11): 5772-5788.

Type 2 diabetes (T2D) is an independent risk factor for cognitive impairment. The dysregulation of hypoxia inducible factor (HIF) signaling in T2D patients results in impaired adaptive responses to hypoxia, thereby accelerating the progression of complications. However, limited knowledge is available regarding its precise function in diabetes-associated cognitive impairment (DACI). Here, elevated HIF-1α levels were observed in brain endothelial cells (ECs) of db/db mice. Functionally, brain ECs-specific knockdown of Hif1a significantly ameliorated T2D-induced memory loss and neuronal damage. Glycolysis in brain ECs was inhibited in this process, as indicated by RNA-seq, leading to decreased hippocampal lactate production through reduced LDHA expression. Notably, T2D patients showed increased cerebrospinal fluid lactate levels, which were strongly associated with their cognitive dysfunction. Intrahippocampal injection of lactate accelerated cognitive dysfunction and impaired adult hippocampal neurogenesis (AHN) in db/db mice. Conversely, reducing hippocampal lactate levels through the intrahippocampal injection of oxamate delayed the onset of memory deficits. Furthermore, asiatic acid was discovered to protect db/db mice from cognitive impairment by decreasing brain endothelial HIF-1α expression and subsequently reducing hippocampal lactate-induced AHN damage. Overall, this study elucidates the inhibiting role played by endothelial HIF-1α-driven lactate in AHN and highlights a potential tactic of targeting HIF-1α in brain ECs for treating cognitive impairment.

The epigenetic landscape of rheumatoid arthritis: Pathogenesis and drug therapeutic potentials

Acta Pharmaceutica Sinica B. 2025, 15(11): 5601-5631.

Rheumatoid arthritis (RA) represents a persistent autoimmune condition distinguished by a multifaceted etiology that encompasses both genetic and environmental factors. Recent progress in understanding the mechanisms behind RA pathogenesis has delved into the critical role of epigenetic regulatory processes, including DNA methylation, histone modifications, and the regulation by microRNAs (miRNAs). These findings provide new insights into the intricate nature of RA and pave the way for innovative therapeutic strategies. This review consolidates the latest developments in the epigenetic regulation of RA, concentrating on how these mechanisms affect the dysregulated signaling pathways associated with the disease. We analyze the roles of specific proteins that function as ‘writers’, ‘erasers’, and ‘readers’ in epigenetic modifications, highlighting their potential as targets for therapeutic intervention. Additionally, in view of the significance of miRNAs in the pathogenesis of RA, we deliberate on their involvement in disease progression and explore miRNA-based treatment strategies. By integrating these diverse epigenetic dimensions, this review offers a comprehensive epigenetic perspective on RA pathogenesis and identifies promising avenues for future research and therapeutic interventions.

Engineered plant extracellular vesicles: Emerging nanoplatforms for combinational cancer immunotherapy

Fucai Chen, Rongrong Bao, Wanyi Yang, Yijing Lu, Jiaxin Guo, Wenjing Chen, Jiale Li, Kuanhan Feng, Wen Zhang, Liuqing Di, Liang Feng, Ruoning Wang

Acta Pharmaceutica Sinica B. 2025, 15(11): 5663-5701.

Plant-derived extracellular vesicles (PDEVs), describe a group of nanoparticles released by plants. These particles are characterized by a lipid bilayer structure containing various proteins, lipids, nucleic acids, and unique metabolites. Although the study on PDEVs is relatively new, having only been around for ten years, they have shown promising development prospects in both basic research and clinical transformation areas. Evidence suggests that PDEVs have excellent application prospects in regulating inflammation and treating tumors. Their distinctive, vesicle-mimicking architecture and stellar biocompatibility render them prime candidates for ferrying various anti-cancer agents, including RNA, proteins, and conventional chemotherapy drugs. Increasingly, studies have shown that PDEVs can be engineered as an innovative platform for combination cancer immunotherapy. Consequently, this paper provides an extensive summary of current developments in engineering methods and strategies for PDEVs in cancer treatment and combined cancer immune therapeutics. The essential characteristics of PDEVs, including the biogenesis process and components, as well as their anti-tumor activity and mechanism, are summarized. Finally, the in vivo safety of PDEVs as delivery vectors and the challenges of scale-up production and clinical transformation are discussed.

Intestinal barrier in chronic gut and liver diseases: Pathogenesis and therapeutic targets

Yongxin Zhang, Yameng Liu, Xinyu Liang, Yingquan Wen, Jingjie Zhao, Yong He, Qing Xie, Cen Xie

Acta Pharmaceutica Sinica B. 2025, 15(11): 5515-5536.

The intestinal barrier is the primary defense that separates the host from the external environment, possessing several crucial physiological functions, including nutrient digestion, absorption, and protection against potentially harmful dietary antigens and pathogenic microorganisms. Nevertheless, various factors, such as diet, medications, circadian rhythm disturbances, gut microbiota, microbial metabolites, and genetic predisposition, can disrupt the intestinal barrier. Such disruption may lead to bacterial translocation, subsequently triggering enterohepatic and systemic inflammation. Impaired intestinal barrier has been implicated in the pathogenesis of numerous diseases, particularly chronic gut and liver diseases. In this review, we will summarize the fundamental functions of intestinal barrier and discuss clinical correlations between intestinal barrier dysfunction and diseases such as colitis, colorectal cancer, and chronic liver diseases including metabolic dysfunction-associated steatohepatitis, alcohol-associated liver disease, and primary sclerosing cholangitis. Additionally, we will also highlight some potential therapeutic strategies aimed at restoring barrier integrity to improve disease management.

Antisense molecules: A promising new therapy for atopic dermatitis

Acta Pharmaceutica Sinica B. 2025, 15(11): 5493-5514.

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder affecting all age groups, especially children, with a prevalence of up to 20% globally. AD remains burdensome and incurable with current therapeutic strategies—ranging from trigger avoidance and skincare to medication—primarily address symptoms rather than disease modification, underscoring the imperative for innovative therapeutic paradigms. RNA-targeted therapies, particularly antisense molecules, have emerged as a transformative approach in precision medicine, with proven clinical success in diseases such as spinal muscular atrophy and familial chylomicronemia syndrome. These therapeutics achieve post-transcriptional regulation unattainable by conventional therapies, enabling direct targeting of messenger RNA (mRNA) and regulatory non-coding RNAs (ncRNAs) implicated in disease pathogenesis. Furthermore, skin is better suited to the antisense modulation due to the relatively easy access to target cells. Numerous studies have explored antisense-based targeting of key drivers in AD progression, yielding promising proof-of-concept results and prompting several early-stage clinical trials. This modality represents a paradigm shift in AD management—one that aligns with the broader revolution in RNA therapeutics reshaping modern medicine. This review critically examines the evolving role of antisense technology in AD, addressing both its mechanistic rationale and the translational challenges that must be overcome to realize its full clinical potential.

Targeting pattern recognition receptors for cancer therapy: Mechanisms and strategies

Acta Pharmaceutica Sinica B. 2025, 15(11): 5537-5600.

Pattern recognition receptors (PRRs) play a crucial role in immune responses, acting as primary sensors for microbial and host-derived signals. PRRs, which include Toll-like receptors (TLRs), retinoic acid-inducible gene 1-like receptors, nucleotide-binding oligomerization domain-like receptors, C-type lectin receptors, and various cytoplasmic DNA sensors, are essential for initiating immune responses that regulate both inflammation and tumor immunity. Recent studies have highlighted their dual roles in cancer, where they can either suppress or promote tumor progression by influencing the tumor microenvironment and modulating responses to immunotherapy. In the context of cancer, PRRs not only activate immune cells but also contribute to immune evasion mechanisms within tumors. Therapeutically, targeting PRRs represents a promising approach for cancer treatment, with related drugs showing potential to enhance the efficacy of existing immunotherapies. Numerous PRR-based agents, particularly TLR agonists, are currently under clinical investigation for their ability to augment antitumor immunity and overcome resistance to immune checkpoint inhibitors. This review examines the molecular mechanisms by which PRRs influence cancer, with a focus on recent advancements in PRR-targeted therapies and their integration with contemporary immunotherapeutic strategies.

Non-blocking anti-PD-L1 nanobody conjugated to TLR7 agonist mediates macrophage/NK cell-associated antitumor effects

Acta Pharmaceutica Sinica B. 2025, 15(7): 3819-3823.