Acta Pharmaceutica Sinica B

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Drugging non-canonical kinases in cancer therapeutics: Molecular targets, underlying mechanisms and small-molecule inhibitors

Acta Pharmaceutica Sinica B. 2026, 16(7): 4196-4232.

Non-canonical kinases (NCKs) are emerging as druggable targets in oncology, yet a comprehensive map linking their molecular mechanisms and targeting strategies to small-molecule modulators is lacking. Based on the hallmarks of cancer, we explain how NCKs buffer replication stress to preserve genome integrity, reprogram metabolic and stress pathways, coordinate angiogenesis and invasion, and support durable remodeling of the immune-tumor microenvironment. We review preclinical progress from hit identification to lead optimization, highlighting exploitable ATP-site and allosteric pockets, targeted protein degradation, and rational dual-node designs, all supported by structural insights and phenotypic discovery. Early clinical signals from mTOR, ATR, and DNA-PKcs inhibitors, along with late-preclinical programs targeting eEF2K, TBK1, FAM20C, TRPM7, and WNKs, reveal context-dependent NCK vulnerabilities. With further exploration of NCK functions and structures, additional targeted drugs are likely to be developed, potentially transforming non-canonical kinase biology into durable precision oncology.
The gut-liver axis in drug-induced liver injury (DILI): Interplay between gut microbiota, intestinal barrier, and immune system

Acta Pharmaceutica Sinica B. 2026, 16(7): 4233-4260.

Drug-induced liver injury (DILI) is an adverse hepatic reaction with a complex etiopathogenesis, involving direct cellular damage by the drug, immune-mediated mechanisms, and host and environmental factors. The gut microbiota has recently been recognized as a key player in human physiopathology. In DILI, animal models and patients have shown significant alterations in gut microbiota composition. Evidence indicates that patients with DILI often present intestinal barrier dysfunction, characterized by increased permeability and the translocation of pathogen-associated molecular patterns (PAMPs) to the liver. This process may contribute to the onset or aggravation of liver injury by triggering harmful immune responses. Furthermore, dysbiosis can alter bacterial metabolite production, thereby affecting intestinal and hepatic homeostasis. The gut microbiota can also modify the efficacy and toxicity of drugs on an individual level, thereby increasing the risk of DILI. This review provides an overview of the current evidence on the mechanisms by which the gut microbiota contributes to inflammation, immune recruitment, and exacerbation of liver damage in DILI. A more in-depth understanding of how the gut microbiota alters intestinal and hepatic homeostasis is essential for advancing our knowledge of DILI pathogenesis, integrating novel biomarkers into clinical practice, and developing microbiota-based interventions.
Molecular glue degraders: Rational design, specificity engineering, and advanced delivery

Acta Pharmaceutica Sinica B. 2026, 16(7): 4261-4284.

Molecular glue degraders (MGDs) have emerged as a transformative modality in the field of targeted protein degradation (TPD), enabling the selective elimination of disease-relevant proteins, including those traditionally considered undruggable. Unlike bifunctional proteolysis-targeting chimeras (PROTACs), MGDs operate through monovalent architectures that induce protein-protein interactions (PPIs) between E3 ligases and neosubstrates, offering advantages in chemical simplicity, cell permeability, and target scope. However, MGD discovery remains serendipitously, and a translational framework that links rational design to predictable selectivity and tissue exposure is still lacking. In this review, we present an integrated framework for advancing next-generation MGDs through three critical dimensions: rational design, specificity optimization, and delivery systems. First, we examined cutting-edge strategies in MGD design, including covalent handle-based reprogramming, PPI-driven stabilization, and multi-site, multi-functional constructs. Second, we explored structure-guided engineering and chemoinformatic models, such as cereblon degron motifs, zone-based design and multiparameter optimization, to improve neosubstrate selectivity while minimizing off-target liabilities. Third, we summarized delivery platforms, including antibody-drug conjugates, nanoparticle-enabled systems, and folate-mediated targeting, which are primarily intended to improve tissue selectivity and targeted distribution, thereby promoting local tissue accumulation. Finally, we discussed emerging opportunities at the intersection of artificial intelligence, structural biology, and systems pharmacology for accelerating MGD discovery and clinical translation. Collectively, these interdisciplinary insights underscore the therapeutic promise of MGDs and lay the groundwork for their next-generation evolution in precision medicine.
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-driven by regulatory science and policy reconstruction: Traditional Chinese medicine (TCM) new drugs accelerate development—A critical review of highlights in registration and regulation of TCM and natural medicine new drugs in China (2021-2025)

Acta Pharmaceutica Sinica B. 2026, 16(7): 4314-4349.

In recent years, China's new round of institution reform has further optimized the drug regulatory system. Relevant departments and institutions involved in traditional Chinese medicine (TCM) regulation have been strengthened. TCM regulatory science, as an emerging interdisciplinary field, has received high regard and experienced rapid development, significantly enhancing TCM regulatory capabilities. Simultaneously, accelerated progress in emerging technologies and production innovation for TCM drug discovery, coupled with the implementation of the National Major Scientific and Technological Special Project for "Significant New Drugs Development" and its translational achievements, have led to a historic turning point in the development of innovative natural TCM drugs over the past five years. Driven by the dual engines of "regulatory science" and "policy restructuring", the development of new TCM drugs has entered a fast lane. Both the quantity and quality of investigational new drug (IND) and new drug application (NDA) registrations and approvals for new natural TCM drugs have shown rapid growth, effectively meeting the public's health demands for TCM products and unmet clinical needs of patients. This study focuses on the development of new TCM drugs during the significant historical phase from 2021 to 2025. It provides a comprehensive overview of new TCM and natural drug applications and regulatory reviews over the past five years, delves into the implementation of the National Drug Regulatory Science Action Plan, and highlights the importance of TCM regulatory science as an emerging interdisciplinary field in accelerating the creation of new TCM drugs. It systematically summarizes the effects of regulatory policies and regulations, the reform of TCM registration classification, specialized TCM registration provisions, and incentive measures such as the National Major Scientific and Technological Special Project for "Significant New Drugs Development". Based on an international perspective, it provides a focused review of recent highlights in TCM new drug development and regulation. This holds significant importance for promoting breakthroughs in TCM new drugs across more disease areas and advancing the international coordination of TCM regulation. The challenge faced in managing the registration of new TCM drugs lies in resolving the conflict between TCM theory and modern drug attributes, while balancing the rapid advancement of traditional medical theory and emerging technologies with the robustness of the drug regulatory framework. In the future, actively advancing research and translation in TCM regulatory science, innovatively establishing benefit-risk assessment systems and standards for new TCM drugs, and accelerating the development of a globally leading regulatory system with Chinese characteristics that aligns with the unique nature of TCM will be particularly crucial for global coordination of TCM regulatory policies, and the modernization and internationalization of TCM.
Hepatic stellate cell enriched Asporin drives liver fibrosis by stabilizing ERH to promote IL-17/MAPK11 signaling

Acta Pharmaceutica Sinica B. 2026, 16(7): 4350-4366.

Liver fibrosis is a pathological process primarily driven by activated hepatic stellate cell (HSC). Single-cell transcriptomics of human fibrotic livers identified ASPN (Asporin) as highly expressed in inflammatory and fibrogenic HSC subsets. Clinically, Asporin was markedly elevated in liver tissue and serum, correlating with fibrosis stage across datasets and cohorts, supporting its potential as a non-invasive biomarker. Functionally, Asporin promoted HSC activation and extracellular matrix (ECM) remodeling, whereas its depletion reduced fibrosis in CCl₄-induced mouse models. Mechanistically, Asporin bound directly to ERH and stabilized it by preventing ubiquitin-mediated degradation. Structural modeling showed Asporin masked ERH's K12 ubiquitination site via hydrogen bonds and hydrophobic interactions. ERH overexpression in HSC activated fibrogenic genes and IL-17 signaling, converging on MAPK11 as a common downstream effector. Notably, ERH knockdown abrogated Asporin-driven profibrotic responses. High throughput screening identified prasugrel, a clinically approved drug, as a potent Asporin suppressor. In CCl₄ and high-fat diet induced fibrosis models, prasugrel alleviated fibrosis, inflammation, lipid accumulation, and portal hypertension by suppressing Asporin and ERH expression. Collectively, these findings define the Asporin/ERH/IL-17/MAPK11 axis as a key mediator of HSC activation and fibrogenesis and highlight prasugrel as a promising anti-fibrotic therapy.
PYGL-driven glycogenolysis impairs microglial autophagic flux via SNAP29 O-GlcNAcylation in Alzheimer's disease

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.
Attenuating AAV-triggered innate immunity in the adult mouse nervous system via cGAS-STING pathway inhibition

Acta Pharmaceutica Sinica B. 2026, 16(7): 4389-4409.

While adeno-associated virus (AAV)-mediated gene delivery has emerged as a promising therapeutic modality for neurological disorders, dose-dependent immune responses remain a critical barrier to clinical translation. Here we reveal the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway as a key mediator of innate immune activation following intracranial AAV administration. Through comparative analyses in genetic and pharmacological intervention models, we demonstrate that STING signaling mediates key neuroinflammatory sequelae including glia reactivation, cytotoxic T cell infiltration, and neuronal injury. Mechanistically, microglia serve as the predominant sentinels detecting AAV immunogenicity via cGAS-STING activation. Therapeutic inhibition of this pathway by either microglia depletion or antagonism of STING by small molecules significantly mitigates high-dose AAV9-induced neurotoxicity while enhancing transgene delivery efficacy. Our work delineates a unified mechanistic framework linking AAV-triggered DNA sensing to neuroinflammatory pathology, and provides two clinically actionable approaches to decouple therapeutic gene delivery from detrimental immune activation in nervous system targeted gene therapy.
Insights into SARS-CoV-2 replication control via targeting the host hijacking function of NSP12

Acta Pharmaceutica Sinica B. 2026, 16(7): 4410-4425.

Nonstructural protein 12 (NSP12), the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, serves as the catalytic core of the viral replication-transcription complex and is pivotal for viral RNA synthesis. Given its essential role, SARS-CoV-2 must precisely regulate intracellular NSP12 levels to support efficient viral replication. However, the mechanisms governing its stability remain poorly understood. Here, we reveal a previously unrecognized viral strategy in which NSP12 hijacks the host chaperone Hsc70 to modulate its own stability. Mechanistically, Hsc70 plays a dual role: mediating NSP12 degradation via chaperone-mediated autophagy (CMA) while also promoting its accumulation. The dynamic balance between these opposing functions determines NSP12 fate. NSP12 can evade CMA-mediated degradation by binding Hsc70 with higher affinity. This disrupts the Hsc70-LAMP2a interaction and shifts Hsc70’s role toward primarily facilitating NSP12 accumulation, thereby enhancing viral replication. We identified Hlyc41 as a potential antiviral agent that disrupts this hijacking mechanism. Hlyc41 competes with NSP12 for binding to the F428 residue of Hsc70, thereby promoting NSP12 degradation and suppressing viral replication. These findings reveal a novel host hijacking mechanism that regulates NSP12 levels and support a promising therapeutic strategy targeting this process.
Targeting FAPα-positive hepatic stellate cells ameliorates the formation of pre-metastatic niche

Sishan Yan, Jingwen Xie, Lijuan Deng, Chulong Chen, Wenfeng Mai, Shuran Fan, Runyu Liu, Maohua Huang, Xiaobo Li, Junqiu Zhang, Shuai Han, Zhongshun Tang, Wenqian Yin, Qun Miao, Chunlin Fan, Wencai Ye, Changzheng Shi, Dongmei Zhang, Ming Qi, Minfeng Chen

Acta Pharmaceutica Sinica B. 2026, 16(7): 4426-4441.

The pre-metastatic niche (PMN) serves as a catalyst for tumor metastasis and colonization, involving communication between immune cells and stromal cells. However, less is known about the specific cell-type and their organ-specific functions in PMN formation, with available therapeutic strategies still limited. Here, we identified a significant expression of fibroblast activation protein alpha (FAPα) in hepatic stellate cells (HSCs) associated with the formation of liver PMN, which was dramatically attenuated in HSC-specific conditional Fap-knockout mice. Mechanistically, tumor cell-derived exosomal miR-2467-3p upregulated FAPα expression in HSCs. FAPα⁺ HSCs promoted IL-18 secretion via NF-κB/NLRP3/caspase-1 signaling pathway, which facilitated extracellular matrix (ECM) remodeling and macrophage recruitment. By targeting FAPα⁺ HSCs, the FAPα-activated prodrug Z-GP-DAVLBH disrupted the PMN and suppressed tumor liver metastasis. Collectively, our study emphasizes the crucial role of FAPα⁺ HSCs in the liver PMN and provides a promising therapeutic strategy for tumor metastasis.

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