Acta Pharmaceutica Sinica B

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How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance

Acta Pharmaceutica Sinica B. 2025, 15(12): 6093-6140.

Cancer remains the leading cause of mortality worldwide. Radiotherapy (RT), a cornerstone of oncological treatment for over a century, has achieved great success in various cancers. However, radioresistance remains the primary factor leading to the failure of radiotherapy. Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure, either by loosening or tightening it. Here, we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal tissue cells. Furthermore, we discuss the regulatory mechanisms of histone modifications and the enzymes on the recruitment of proteins that recognize histone modifications. Consequently, these processes substantially affect the radiosensitivity of tumors. In addition to cancer cells, we highlight the intricate interplay between histone modification and radiosensitivity, both within and beyond the cancer cells. Meanwhile, various drugs targeting histone modifications emerge as a promising therapeutic strategy to overcome radioresistance of tumors as well as radioprotection. The combination of histone modification inhibitors with radiotherapy presents a novel approach to enhance cancer treatment outcomes in clinical practice. Nevertheless, the underlying mechanisms through which histone modifications influence cancer radiosen-sitivity require further elucidation to identify novel targets for radiotherapeutic intervention.
Emerging epigenetic modifications in renal fibrosis: From mechanisms to treatments

Acta Pharmaceutica Sinica B. 2025, 15(12): 6141-6162.

Chronic kidney disease (CKD) has emerged as a formidable global health challenge, with a marked increase in its incidence, prevalence, and mortality rates. Renal fibrosis is a central pathophysiological process that drives the progression of CKD to end-stage renal disease. Despite its crucial role in CKD progression, effective clinical interventions to delay or mitigate renal fibrosis remain limited. A deeper understanding of the molecular mechanisms underlying renal fibrosis, along with the identification of potential drug targets and the development of novel therapeutics, holds immense research significance and clinical value for the prevention and treatment of CKD. In recent years, epigenetic research has garnered widespread attention and plays a pivotal role in various disease processes. Against this back-drop, the mechanisms by which epigenetic modifications exert their effects on renal fibrosis are gradually being elucidated, offering novel insights into the understanding of CKD. In this review, we summarize and analyze the intricate regulatory network of epigenetic modifications in renal fibrosis. We explore the promising antifibrotic effects demonstrated by various epigenetically modified drugs in fibrotic kidney models and discuss the challenges and opportunities in current research. These findings provide crucial insights for a deeper understanding of the molecular mechanisms underlying renal fibrosis and the development of novel therapeutic approaches.
Graph neural networks driven acceleration in drug discovery

Acta Pharmaceutica Sinica B. 2025, 15(12): 6163-6177.

Graph neural networks (GNNs) are revolutionizing drug design processes. Over the past five years, GNNs have emerged as transformative tools by accurately modeling molecular structures and interactions with binding targets. Breakthroughs in predicting molecular properties, drug repurposing, toxicity assessment, and interaction analysis, along with generative GNNs enhancing virtual screening and novel molecule design, have significantly sped up drug discovery. These GNN-driven innovations improve predictive accuracy, cut development costs, and reduce late-stage failures. This review focuses on the interdisciplinary integration of GNNs throughout the discovery process, including lead discovery and optimization, synthetic route design, drug–target interaction prediction, and molecular property profiling, while critically evaluating the challenges in translational medicine.
m⁶A readers: Promising therapeutic targets in cancer treatment

Acta Pharmaceutica Sinica B. 2025, 15(12): 6178-6198.

N⁶-methyladenosine (m⁶A) represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation, significantly impacting gene expression through the selective recognition by m⁶A reader proteins. Aberrant expression of m⁶A readers has been associated with cancer progression, contributing to tumor growth, metastasis, drug resistance, and immune evasion. With the increasing research on m⁶A readers, the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy. This review delineates the classification and functional roles of m⁶A readers across various cancers. Furthermore, we summarize and discuss the recent progress in the development of small-molecule inhibitors, with a focus on the medicinal chemistry perspectives. We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m⁶A readers for innovative cancer therapeutics.
Artificial intelligence for radiopharmaceutical and molecular imaging

Acta Pharmaceutica Sinica B. 2025, 15(12): 6199-6221.

Artificial intelligence (AI)-driven data-centric paradigms are catalyzing a paradigm shift in radiopharmaceutical development and molecular imaging, two pivotal technologies that underpin precision nuclear medicine. This review focuses on the cutting-edge applications of AI in radiopharmaceutical discovery and molecular image analytics, and systematically investigates the technical principles and typical cases of Deep Learning algorithms (e.g., Graph Neural Networks (GNNs), Generative Adversarial Networks (GANs), and Transformer Models) in target identification, ligand design, pharmacokinetic optimization, and image reconstruction and enhancement. By integrating multi-omics data and 3D structural information, AI can significantly improve the accuracy of target affinity prediction for radiopharmaceuticals and accelerate the design of novel ligands. In the field of molecular imaging, AI-driven low-dose single-photon emission computed tomography (SPECT) and positron emission tomography (PET) image reconstruction, tumor segmentation, and quantitative analysis techniques have significantly improved the diagnostic efficiency and accuracy, providing a reliable basis for individualized treatment. In addition, the paper discusses data privacy, model generalization, and ethical challenges faced by AI in clinical translation, and looks forward to the future direction of multidisciplinary integration (e.g., combining AI with radiochemistry and nuclear medicine) and technological innovations, which will help precision medicine leap from theory to practice.
Recent advances in engineering nano/microrobots for tumor treatment

Acta Pharmaceutica Sinica B. 2025, 15(12): 6222-6252.

Until now, although nanomedicines have gained much success in tumor treatment by reducing severe toxic side effects of drugs and improving the therapeutic efficiency of drugs, they are still faced with thorny challenges in targeted drug delivery including insufficient targeting accuracy, poor penetration into tumor core, and systemic toxicity issues. Recently, engineering nano/microrobots with multiple remarkable properties such as real-time sensing, interacting and manipulating capabilities, and programmability, have received increasing attention in biomedical applications ranging from disease diagnosis, targeted drug delivery, medical imaging, and surgery. More importantly, in different driven modes, nano/microrobots are capable of performing a wide variety of powerful functions, such as enhancing tissue penetration and payload retention in deep-seated tumors with active navigation, being programmable to release drugs or performing specific tasks directly at the tumor site with high precision and accuracy, automating repeated tumor treatment without the need for frequent interventions, and minimizing out-of-target tissue damage, leading to a huge exploration potential in tumor treatment. In this review, we delve into the recent progress and the development direction of nano/microrobots for tumor treatment and emphasize the working mechanisms and the unique functionalities of different driven modes in detail. Meanwhile, we elaborate on the application of nano/microrobots fabricated from various types of materials in tumor therapy. Finally, the key factors to be considered in the clinical translation of the above nano/microrobots are proposed.
Site-specific PEGylation of proteins: Insights into structural and functional changes

Acta Pharmaceutica Sinica B. 2025, 15(12): 6253-6273.

Polyethylene glycol (PEG) is a polymer with different molecular weights formed by the polymerization of ethylene oxide monomers. Due to its ability to significantly reduce the immunogenicity of protein drugs and extend their half-life, as well as its high safety profile, it has been approved by the U.S. Food and Drug Administration (FDA) as the gold standard for delivering protein drugs. Although numerous PEGylated protein drugs have been marketed, the focus of research on PEGylated protein drugs has primarily been on reducing immunogenicity and extending in vivo circulation half-life. However, the understanding of how PEG modification affects the structure and function of proteins is still limited, with “activity” often being the sole criterion for evaluating changes in protein structure and function. A deeper exploration of the existence and interaction between PEG chains and proteins is of great significance for understanding the properties exhibited by PEGylated proteins. This review summarizes strategies for PEG site-specific modification of proteins, the interaction states between PEG and proteins, and the effects of PEG chains on protein spatial structure, solubility, activity, and thermal stability. It also summarizes the characterization techniques for PEG–protein interactions, aiming to predict or explain the functions of PEGylated protein drugs through the analysis of PEG–protein interactions.
ROS-scavenging nanomaterials as emerging tools for bone tissue regeneration: A comprehensive review of recent progress

Acta Pharmaceutica Sinica B. 2025, 15(12): 6274-6306.

Bone defects, characterized by a loss of skeletal structure integrity, represent a prevalent clinical challenge affecting millions of patients. While bone autografts and allografts offer potential solutions, limitations, including donor scarcity, immune rejection, anatomical constraints, and complications arising from host comorbidities such as diabetes, often lead to unsatisfactory outcomes. This necessitates the need for alternative treatments. Researchers have identified that reactive oxygen species (ROS) play a crucial role in bone regeneration. Although physiological ROS levels are essential for normal healing, excessive ROS accumulation disrupts the balance between bone formation and resorption, hindering regeneration. Antioxidants can mitigate oxidative stress by scavenging ROS or inhibiting their formation, thereby restoring the equilibrium between bone formation and resorption. Advances in nanotechnology have enabled the development of various ROS-scavenging nanomaterials with enhanced therapeutic efficacy. These nanomaterials either function as delivery platforms for conventional antioxidants or as direct ROS-neutralizing agents through intrinsic redox or enzyme-mimicking properties. This review comprehensively summarizes ROS-scavenging nanomaterials for bone tissue regeneration, focusing on their design strategies, underlying mechanisms, applications, and potential for clinical translation.
Ferroptosis meets cancer immunotherapy: Overcoming the crosstalk challenges through advanced drug delivery strategies

Acta Pharmaceutica Sinica B. 2025, 15(12): 6307-6341.

The integration of ferroptosis induction with cancer immunotherapy has emerged as a promising approach in oncology, offering dual mechanisms to overcome therapeutic resistance and tumor heterogeneity. Nevertheless, the dynamic and complicated crosstalk between ferroptosis processes and immune regulation in tumor microenvironments presents both opportunities and challenges. By inducing lipid peroxidation in tumor tissues, ferroptotic tumor cell death can stimulate immunogenicity. Nevertheless, excessive lipid peroxidation may paradoxically impair the functionality of multiple immune cells, thereby presenting crosstalk challenges in therapeutic strategies. To address these crosstalk challenges, several advanced drug delivery strategies have been proposed, such as immunostimulatory active pharmaceutical ingredients co-delivery, tumor-targeted delivery, and stimuli-responsive delivery. These drug delivery strategies demonstrate dual therapeutic efficacy by synergistically potentiating ferroptosis induction in malignant cells while concurrently mitigating immunotoxicity and even augmenting antitumor immunity. This review offers detailed insights into the crosstalk between ferroptosis and tumor immunity, along with a guiding overview of the three delivery strategies. The current obstacles and translational potential were thoroughly analyzed, providing valuable perspectives for future research.
Progress in peptide and protein therapeutics: Challenges and strategies

Acta Pharmaceutica Sinica B. 2025, 15(12): 6342-6381.

Peptide- and protein-based therapeutics offer realized and potential benefits to health, due to their potent bioactivity, high specificity, and favorable safety characteristics. However, their widespread clinical application is constrained by inherent limitations, including rapid enzymatic degradation, poor membrane permeability, and a reliance on parenteral administration, which reduces patient adherence. To overcome these challenges, extensive research has explored non-invasive delivery strategies, including topical, transdermal, and oral formulations. Despite promising advances in these delivery strategies, they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics, such as enzymatic degradation in the gastrointestinal tract, limited epithelial transport, and inherently low systemic bioavailability. This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy. It critically examines key challenges associated with various administration routes, including topical, transdermal, oral (including delivery targeting the brain), and others. Furthermore, it explores innovative strategies to enhance peptide and protein stability and bioavailability, including chemical modifications, enzyme inhibitors, penetration enhancers, physical delivery technologies, and advanced nanoparticulate formulations. Additionally, emerging trends in formulation optimization, regulatory considerations, and translational pathways for clinical implementation are discussed. By addressing these critical challenges and highlighting recent advances, this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy, and enhanced patient adherence, which is needed to fully realize the true potential of this class of therapeutics.

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