Acta Pharmaceutica Sinica B

Loss of TET2 sulfhydration results in destabilization of TET2 and down-regulation of the immune response in melanoma

Acta Pharmaceutica Sinica B. 2026, 16(8): 5183-5199.

Loss of TET2 protein leads to reduced DNA 5-hydroxymethylation (5-hmC), a key epigenetic alteration in melanoma, yet the regulatory mechanism governing TET2 stability remains unclear. Here, TET2 sulfhydration was analyzed in clinical melanoma samples, with sulfhydration sites identified by mass spectrometry, and the effects of active sulfur on TET2 stability, catalytic activity, and global 5-hmC assessed in melanoma cells. TET2 sulfhydration was significantly depleted in melanoma and further reduced in advanced stages. The cysteine-rich zinc finger domain at C1186/1202 was identified as the key sulfhydration site, which is essential for maintaining TET2 stability and enzymatic activity. Active sulfur restored TET2 sulfhydration, up-regulated TET2 protein, and reprogrammed global DNA hydroxymethylation. Notably, active sulfur synergized with anti-PD-1 therapy by enhancing IFN-γ-induced Th1-type chemokine and MHC-I expression in melanoma cells, thereby boosting CD8⁺ T-cell-mediated immune responses. These findings demonstrate that TET2 sulfhydration at C1186/1202 is a crucial post-translational modification for TET2 stability and function, playing a key role in epigenetic regulation and antitumor immunity, and highlight the immunoadjuvant potential of reactive sulfur species in melanoma immunotherapy.

Inflammation in atherosclerosis: Drivers, mechanisms and therapies

Acta Pharmaceutica Sinica B. 2026, 16(8): 4770-4807.

Atherosclerosis has traditionally been considered a lipid-driven disease. However, emerging evidence highlights the central role of inflammation in the development of atherosclerosis. Multiple cell types, including endothelial cells, macrophages, and other immune cells, interact within lesions to form a chronic inflammatory microenvironment. Unhealthy lifestyle, smoking and metabolic disorders like hyperlipidemia, hyperglycemia, and their derived pro-atherogenic products drive vascular inflammation. Recent evidence reveals that high-sensitivity C-reactive protein surpasses LDL-cholesterol in predicting future cardiovascular risk. Combining lipid-lowering with anti-inflammatory therapies significantly reduces event recurrence, underscoring the need for targeted drugs. Promising results have emerged from trials of anti-inflammatory agents. Statins and other lipid-lowering drugs also exhibit anti-inflammatory properties. However, cholesterol-independent strategies face challenges like infection risk from immunosuppression, requiring extensive safety evaluation. Enhancing intrinsic resilience mechanisms is a promising alternative in combating vascular inflammation and atherosclerosis. High-throughput screening accelerates drug development, while induced pluripotent stem cell-derived vascular organoids better simulate human atherosclerosis pathobiology, improving preclinical predictions. Research on organ interaction networks and trained immunity offers novel therapeutic targets. In this comprehensive review, we provide a state-of-the-art synthesis of the drivers, mechanisms, and potential therapies of atherosclerosis by targeting inflammation, with an aim to reducing residual cardiovascular risk in the post-statin era.

DeepHalo: Deep learning-powered exploration of halogenated metabolites uncovering antibacterial depsipeptides

Shanshan Chang, Xin Qi, Mengyuan Wang, Xinyue Huang, Ning He, Mingxu Chen, Qing Lv, Jiahan Wang, Yu Du, Shuchen Wang, Yihong Li, Quanxiu Gao, Xinran Chen, Xingxing Li, Bin Hong, Yunying Xie

Acta Pharmaceutica Sinica B. 2026, 16(8): 5034-5052.

In the omics era, confident high-throughput analytical tools are crucial for the efficient identification of metabolites. Here, we present DeepHalo, a deep learning-integrated and hierarchically optimized workflow designed for high-throughput exploration of halogenated metabolites from high-resolution mass spectrometry-based metabolomics. DeepHalo leverages deep learning models combined with a comprehensive scoring to enhance the reliability of halogen predictions. It integrates PyOpenMS for fast isotope pattern detection and incorporates a halogen-based dereplication algorithm with GNPS molecular networking to efficiently exploit and annotate halogenates from complex biological matrices. To validate its performance, DeepHalo was applied to explore halogenated metabolites from 1296 microbial culture crudes, leading to the discovery of six families of structurally diverse halogenated molecules. This included a new class of cyclic depsipeptides, aglomycins A‒E, featuring rare 3-chloroanthranilic acid and/or epoxyvaline blocks. Additionally, a plausible biosynthetic pathway of aglomycins was proposed through bioinformatics analyses and targeted gene knockout experiments. Bioassays revealed that aglomycin A exhibits synergistic antibacterial activity with linezolid against vancomycin-resistant Enterococcus faecium (VRE) both in vitro and in vivo. We envision that DeepHalo, a user-friendly standalone executable freely available at https://github.com/xieyying/deephalo/releases/tag/DeepHalo_V1.0.0, will become a powerful tool for accelerating the discovery of halogenated “dark matter”.

PYGL-driven glycogenolysis impairs microglial autophagic flux via SNAP29 O-GlcNAcylation in Alzheimer's disease

Yi Ding, Shi-Yao Li, Wen-Feng Zhang, Mao-Mao Chu, Xue-Jie Wang, Yu-Ge Zhang, Hui-Wen Zhang, Yu-Tong Zhang, Lu Xu, Xue Liu, Tsuyoshi Morita, Otto Baba, Zi-Jian Ren, Yong-Jie Zhang, Zhi-Yuan Zhang, Lei Li

Acta Pharmaceutica Sinica B. 2026, 16(7): 4367-4388.

Aberrant metabolic alterations underlie microglial dysfunction, which plays an important role during neurodegenerative progression. However, the role of aberrant glycogen metabolism remains elusive. Here, we identified glycogen accumulation and upregulated glycogenolytic enzymes in brain microglia from patients with Alzheimer's disease (AD) and transgenic animal models. Particularly, the principal microglial glycogenolytic enzyme PYGL exhibited the most notable spatiotemporal upregulation during disease progression. Specific knockdown of microglial PYGL ameliorated neuropathological changes and cognitive deficits in AD mice. Bioinformatics analysis and experimental validation confirmed that enhancing microglial autophagic flux-dependent Aβ clearance was the underlying mechanism. Furthermore, among all possible glycogenolytic pathways, PYGL downregulation primarily reduced hexosamine biosynthesis pathway activity, diminished UDP-GlcNAc and O-GlcNAcylation of the autophagy key protein SNAP29, and thereby facilitated formation of the SNARE complex, which is essential for autophagosome-lysosome fusion. These findings reveal a glycogenolysis-driven post-translational pathway regulating microglial autophagy, establishing PYGL as a therapeutic target for AD.

In vitro transcribed circRNA as a therapeutic agent for cancer

Xu Shi, Yue Zhao, Yunkai Tang, Gang Fu, Chen Qian, Feng Li, Zheyu Yang, Wenguo Cui, Wei Cai

Acta Pharmaceutica Sinica B. 2026, 16(7): 4285-4313.

RNA therapy represents an innovative approach for cancer treatment, with several RNA-based therapeutics having received approval from the US Food and Drug Administration. Circular RNA (circRNA), a closed-loop RNA molecule characterized by its high stability, plays a significant role in regulating biological processes by modulating gene expression and facilitating protein translation. Given its unique structure and diverse functionalities, the delivery of exogenous circRNA has emerged as a novel strategy for cancer therapy. This review examines the mechanism underlying circRNA-mediated tumor therapy, emphasizing its various biological roles, including that of an RNA sponge, aptamer, gene editing tool, and facilitator of protein translation, and explores the therapeutic potential in oncology. The review provides a comprehensive discussion on the synthesis strategies of exogenous circRNA, based on T4 DNA ligase and the permuted introns-exons (PIE) method, as well as elucidating the purification techniques. This article also reviews prominent carriers currently employed for circRNA delivery, such as lipid nanoparticle (LNP), exosomes, and virus-like particle (VLP), with a particular emphasis on their application in cancer-targeted therapies. Finally, the review summarizes key challenges currently in the field along with viable solutions. It highlights the prospective role of artificial intelligence in enhancing circRNA delivery to facilitate precise cancer treatment based on exogenous circRNA.

Dual-pathway induction of pyroptosis via biomineralized-like nanoparticles trigger potent immunotherapy against tumor

Jiaxing Feng, Kun Xiong, Yuan Xue, Yating Wang, Xiuhua Wu, Qing Lin, Xun Sun, Huile Gao, Zhirong Zhang, Tao Gong

Acta Pharmaceutica Sinica B. 2026, 16(7): 4725-4738.

Pyroptosis, a highly pro-inflammatory form of immunogenic cell death, holds great promise for cancer treatment. However, its efficacy in cancer cells is often limited due to low efficiency and cellular complex pro-survival mechanisms. In this study, we address this challenge by an integrated nanoplatform simultaneously activating two pathways of pyroptosis. Manganese ions and imidazole serve as a framework to coordinate glucose oxidase (GOx) and epigallocatechin gallate (EGCG) into stable biomineralized-like nanoparticles. We hypothesize that EGCG, as an inhibitor of DNA methyltransferase, may restore the expression of Gasdermin E (GSDME), a crucial component of pyroptosis activated by cleaved caspase-3. Through glucose consumption, GOx triggers both the caspase-1/Gasdermin D (GSDMD)-mediated and caspase-3/GSDME-mediated pathways of pyroptosis simultaneously, leading to efficient pyroptosis in cancer cells and a robust anti-tumor immune response, accompanied by the upregulated expression of PD-L1. Our results reveal that integrating this strategy with immune checkpoint inhibitors results in a tumor inhibition rate exceeding 80% across several “cold” tumor models, a 20% cure rate in the CT26 unilateral tumor model, and 5/8 distant tumors remaining free of recurrence upon re-challenge. In conclusion, this dual-pathway induction of pyroptosis offers a novel and promising strategy for enhancing cancer immunotherapy.

Bladder adaptive hydrogel scaffold with dual release, antimicrobial, immunomodulatory, and repair: DRIVER for urinary tract infections

Acta Pharmaceutica Sinica B. 2026, 16(7): 4706-4724.

Urinary tract infections (UTIs), especially complex or recurrent cases, present a significant challenge. Systemic antibiotics often fail to provide adequate local drug concentrations, leading to limited efficacy and relapse. Local delivery is hindered by the bladder’s dynamic environment, causing rapid drug clearance. To address this, a hydrogel scaffold, DRIVER (dual release, repair of tissues, immunomodulation, vesical adaptation, elimination of pathogens, and regulation of autophagy), is designed for sustained release in sync with the infection cycle. DRIVER forms a self-regulating 3D network through dynamic bonding and metal ion coordination, ensuring stable release and adaptability. It delivers a biphasic release profile comprising an initial antimicrobial burst that rapidly suppresses acute infection, followed by a 7-day sustained release phase. In vitro, DRIVER retained potent antibacterial and antifungal activity against planktonic, biofilm-embedded, and intracellular pathogens, including drug-resistant strains. Notably, the hydrogel also promoted bladder and kidney repair by modulating mitochondrial activity and autophagy, pathways essential for restoring urothelial integrity. DRIVER achieved >3 log reductions in bacterial and fungal burdens, normalized urinary function, and markedly attenuated systemic and tissue inflammation. Histological analyses confirmed robust architectural recovery in both the bladder and kidney. Together, these findings establish DRIVER as a compelling therapeutic strategy for complex UTIs.

Engineering an immuno-nanoprodrug: Photo-controlled pyroptosis synergizing with acid-activatable immunometabolic blockade for potent cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(7): 4616-4633.

Although immunotherapy has revolutionized cancer treatment, antitumor immunological responses remain limited by insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. Herein, pyroptosis induction is integrated into a photosensitizer to potentiate tumor immunogenicity. In this part, artesunate is disclosed to increase GSDME and modified to synthesize its ROS-cleavable prodrug, which is then installed into the self-assembled photosensitizer, resulting in a novel oil-in-water nanoplatform (BDP-pATS). The cytotoxicity, pyroptosis feature and potentiated GSDME induced by BDP-pATS are well confirmed. Subsequently, a novel acid-activatable adenosine-A2AR inhibitor is synthesized and further installed into the aforementioned platform to obtain BDP-pATS-aA2Ai, manipulating immunometabolic strategy to counterbalance the enhanced adenosine caused by pyroptosis. Such a photo-controlled and acid-activatable nanoprodrug enhances cytotoxic T cell functions while restrains regulatory T cell activities, leading to potent effects toward primary and abscopal tumor inhibition. In addition, BDP-pATS-aA2Ai also manifests desirable performance on pulmonary metastasis and tumor recurrence mouse model. To the best of our knowledge, this study presents the first concept of blocking adenosine-A2AR pathway during pyroptosis occurrence. Collectively, this work strategically combines immunometabolic interception, pyroptosis induction, photodynamic therapy and epigenetic regulation, emphasizing the significance of comprehensive therapy, which should open up a new viewpoint for cancer immunotherapy.

Photobiomodulation-reprogrammed extracellular vesicles delivered via a biodegradable microneedle patch promote cardiac repair by enhancing glycolytic metabolism

Acta Pharmaceutica Sinica B. 2026, 16(7): 4592-4615.

Stem cell-derived extracellular vehicles (EVs) hold great therapeutic potential for myocardial infarction (MI). However, the efficient production of EVs with high bioactivity remains a critical bottleneck limiting their clinical translation. Here, we demonstrate that conditioned photobiomodulation (PBM) with green light is capable of activating human embryonic stem cells (hESCs) to secrete more EVs with superior cardioprotective activity. These PBM-reprogrammed hESC-EVs improve cardiac recovery in a murine MI model by promoting cardiomyocyte proliferation and angiogenesis while inhibiting apoptosis. Notably, we validate that these EVs similarly enhance the survival and proliferation of human cardiomyocytes, underscoring their translational potential. Further analysis reveals that this benefit is due to the higher miR-423-3p content in reprogrammed hESC-EVs, which enhances glycolytic metabolism and restores mitochondrial function by regulating the ZBTB7A/PKM2 axis. Moreover, we synthesize a methacryloyl hydrogel microneedle patch with superior biocompatibility, biodegradability, and mechanical strength for loading hESC-EVs, and convey the patch to the infarcted heart via a modified delivery apparatus. This system ensures the precise and sustained delivery of EVs to ischemic myocardium, offering a potent treatment for MI. Collectively, this optical and biomaterials-based approach efficiently prepares EVs with higher cardioprotective activity, providing new therapeutic strategies for heart disease.

High-throughput ligand discovery in living cells using the cellular protein stability enhancement assay

Acta Pharmaceutica Sinica B. 2026, 16(7): 4524-4538.

Target-based drug screening typically relies on biochemical or affinity-based assays to identify compounds that modulate or bind to purified target proteins in vitro. However, additional cellular validation is essential to confirm genuine drug-target engagements. Integrating screening and validation within a single cellular assay could greatly expedite the drug discovery process. Herein, we developed a cellular ligand discovery method called CPSEA (cellular protein stability enhancement assay), which leverages the biophysical principle of ligand-induced stabilization of target proteins containing destabilizing mutations. Using CPSEA, we identified arteannuin B and colchicine as novel ligands for FKBP12 and KRASG₁₂S, respectively. Importantly, we introduced both experimental and computational strategies to identify destabilizing mutations, thereby broadening the applicability of CPSEA for target proteins with and without known stabilizing ligands. Overall, CPSEA represents a powerful cell-based screening strategy with significant potential in target-based drug discovery.