Acta Pharmaceutica Sinica B

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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.
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.
Targeting renal tubular epithelial cells via a dual functionalized oligosaccharide self-assembly in the management of acute and chronic kidney diseases

Acta Pharmaceutica Sinica B. 2025, 15(12): 6607-6625.

The kidneys are susceptible to hypoxia, proteinuria, and toxins, which can trigger acute kidney injury (AKI). Maladaptive repair of AKI results in the development of chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) represents a pivotal mechanism underlying renal interstitial fibrosis (RIF). Myofibroblasts represent the primary effector cells of RIF with over 30% derived from renal tubular epithelial cells (RTECs). RTECs play a crucial role in CKD by generating part of EMT, while Snail1 is an effective inducer of EMT. Therefore, silencing Snail1 in RTECs and blocking the EMT process represents an original approach for treating RIF. Here, the positively charged l-arginine (L-Arg) and the hydrophobic fragment stearic acid (SA) were introduced on the chitosan oligosaccharide to afford a dual-targeted COA-SA micelle via size-, charge- and active targeting effects. The micelle overcomes the substantial disparity in physical and chemical properties between hydrophilic nucleic acid macromolecules and the anti-inflammatory small molecule celastrol and successfully establishes a codelivery platform. In vivo, COA-SA micelles can traverse the blood circulation, and glomerular filter, and overcome intracellular barriers to achieve efficient and precise drug delivery to RTECs. This results in the successful reversal of the EMT process in RTECs, thereby achieving a favorable anti-fibrosis effect.
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.
Injectable hydrogel-mediated co-delivery of oncolytic adenovirus and melphalan for retinoblastoma control and vision preservation

Acta Pharmaceutica Sinica B. 2025, 15(12): 6638-6656.

Retinoblastoma (RB) is the most common primary ocular malignancy in children, arising from the developing retina. While higher doses of local chemotherapy have improved tumor control, concerns regarding retinal toxicity and the development of chemoresistance remain significant. Oncolytic adenovirus (OA) presents a promising therapeutic approach for RB, but rapid clearance often limits its therapeutic effects. In this study, we engineered a genetically modified OA derived from human adenovirus 5 (Ad5), designed to selectively target and lyse RB cells. The combination of OA with low-dose melphalan demonstrates an enhanced antitumor effect, while minimizing retinal toxicity. In vitro and in vivo experiments demonstrated that melphalan significantly enhanced the antitumor effect of OA and extended ocular survival. More importantly, we developed a biocompatible injectable hydrogel delivery system based on the covalent coupling of collagen and aldehyde-modified cyclodextrin, which effectively enhances the loading efficiency of melphalan and enables sustained co-delivery of OA and melphalan. The mouse RB tumor model confirmed that this hydrogel system (OA-Mel@CCA) achieved localized and sustained delivery of both therapeutics, effectively controlling tumor growth and preventing brain metastasis. Additionally, retinal structure and function were notably preserved in mice treated with OA-Mel@CCA, with no observed retinal toxicity. These findings suggest that the injectable hydrogel-based co-delivery of melphalan and oncolytic adenovirus could represent a promising strategy for RB treatment.
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.
Development of a novel ¹⁸F-labeled reversible-binding radioligand for imaging monoacylglycerol lipase with positron emission tomography

Acta Pharmaceutica Sinica B. 2025, 15(12): 6714-6726.

Monoacylglycerol lipase (MAGL) constitutes a crucial serine hydrolase within the endocannabinoid system, which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders. While MAGL inhibitors have entered the clinical arena, a highly selective and MAGL-specific positron emission tomography (PET) ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients. Accordingly, this study aimed to develop a new series of reversible MAGL inhibitor candidates, based on a piperazinyl azetidine diamide scaffold. Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates. Subsequently, it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging, as well as ex vivo biodistribution and metabolite analysis experiments in rodents. Compound 3 exhibited a heterogeneous radioactivity distribution, favorable brain uptake, and excellent in vivo binding specificity. Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of [¹⁸F]3 in rat brains. In conclusion, [¹⁸F]3 ([¹⁸F]MAGL-2011) has the potential to serve as an effective MAGL PET ligand.
Preclinical characterization and anti-RSV efficacy of an oral C-nucleoside derivative

Acta Pharmaceutica Sinica B. 2025, 15(12): 6727-6730.
New leap of BRD9 inhibitor: Imidazole substituents making BRD9 inhibitors excellent drug candidates for AML

Acta Pharmaceutica Sinica B. 2025, 15(12): 6741-6742.

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