Acta Pharmaceutica Sinica B

REEP6 promotes colorectal cancer glycolysis and tumorigenesis through PRMT5-mediated PGAM1 arginine methylation

Acta Pharmaceutica Sinica B. 2026, 16(2): 948-965.

Metabolic reprogramming is a notable hallmark of cancer biology, especially aerobic glycolysis. Some clinical trials attempt to target cancer metabolism to develop therapeutic agents. However, the results have been not satisfactory. Here, we report that REEP6 is significantly upregulated and promotes glycolysis and tumorigenesis in CRC. Moreover, REEP6, as a molecular scaffolder, bridges the PRMT5–PGAM1 complex, which enhances the PRMT5-mediated symmetric dimethylarginine (SDMA) of PGAM1 at R40. The methylated PGAM1 possesses dramatically enhanced enzymatic activity and therefore boosts glycolytic flux in CRC cells. More than that, our results showed that combined treatment with specific shRNA and inhibitors exhibits synergistic anti-tumor efficacy in CRC, which may shed light on the development of a promising therapy in CRC.

Blocking TRIM47-mediated HNF4α degradation suppresses hepatocellular carcinoma progression

Huanyu Hong, Mengchao Xiao, Hui Qian, Siqi Tan, Sihan Wu, Fang Liu, Xialu Hong, Shuqing Liu, Chenhong Ding, Keqi Wang, Weifen Xie, Xin Zhang

Acta Pharmaceutica Sinica B. 2026, 16(2): 913-929.

Previous studies have highlighted the downregulation of hepatocyte nuclear factor 4alpha (HNF4α) as a critical event in the pathogenesis of HCC. However, the mechanism of its degradation in HCC remains unclear. Tripartite motif 47 (TRIM47), a typical E3 ubiquitin ligase of the TRIM family, has been implicated in various tumors, yet its specific role in HCC progression is not fully elucidated. In this study, HNF4α was identified as a potential target of TRIM47 by using co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis. TRIM47 facilitates the degradation of HNF4α by mediating K48-linked ubiquitination at lysine 470. Abrogation of HNF4α ubiquitination attenuated the promoting effect of TRIM47 on HCC malignancy. Molecular docking studies and Co-IP experiments revealed that K342, W349, and E353 of HNF4α, along with K534 and K600 of TRIM47, are crucial for their interaction. A small molecule, CZ-2401, was selected as a potent inhibitor of the TRIM47–HNF4α interaction through virtual screening and pharmacological activity validation. CZ-2401 effectively stabilizes HNF4α protein in HCC cells and ameliorates TRIM47-driven HCC progression in vivo. Taken together, our research elucidates that targeting TRIM47–HNF4α interaction is a potential therapeutic strategy for HCC, and identifies CZ-2401 as a potent inhibitor of HNF4α degradation and a promising candidate for HCC therapy.

Targeting oncogenic K-RAS mutants with small-molecule degrader XMU-MP-9 through NEDD4-1

Taoling Zeng, Tingting Jiang, Baoding Zhang, Ting Zhang, Wanjun Dai, Xun Yin, Yunzhan Li, Zhuoran Yu, Caiming Wu, Yaying Wu, Ximin Chi, Xianming Deng, Hong-Rui Wang

Acta Pharmaceutica Sinica B. 2026, 16(2): 979-993.

K-RAS mutations represent a most prevalent oncogenic alteration in human cancers. Despite tremendous efforts, it remains a big challenge to develop strategies that specifically target the oncogenic K-RAS mutants. Here, taking advantage of our previous finding that NEDD4-1 is an E3 ubiquitin ligase for wild-type RAS proteins, we developed a compound XMU-MP-9 that can promote ubiquitination and degradation of various K-RAS mutants including K-RASG¹²V, and significantly inhibit proliferation and tumor development of K-RAS mutant harboring cells. Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of NEDD4-1 and an allosteric site of K-RAS to enhance NEDD4-1 and K-RAS interaction, and to induce a conformational change of NEDD4-1/K-RAS complex to allow NEDD4-1 targeting K128 of K-RAS for ubiquitination. Hence, our study presents an effective way to degrade K-RAS mutants to prevent tumor development.

Hyperimonates A and B, a pair of unprecedented polyprenylated acylphloroglucinols from Hypericum monogynum: Structural elucidation, total synthesis, and lipid-lowering activity

Acta Pharmaceutica Sinica B. 2026, 16(2): 1009-1021.

Hyperimonates A (1) and B (2), two minor polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented hexahydro-1H-cyclopenta[c]furan-1-one and 2-oxabicyclo[2.2.1]heptane ring system were isolated from Hypericum monogynum. To obtain adequate materials for biological research, the asymmetric total syntheses of 1 and 2 were completed from commercially available geraniol via a bioinspired strategy that features an Au(I)-catalyzed carbometallic cascade cyclization and a Mn(III)/Cu(II) mediated oxidative radical cyclization as vital steps. Biological study implied that compound 1 showed excellent lipid-lowering activity in vitro via inhibiting two signaling pathways, Notch and PPAR, further verified by non-alcoholic fatty liver disease (NAFLD) zebrafish model. These findings provide a new structural template for the treatment of NAFLD and asymmetric synthetic approaches could also facilitate further evaluation for drug development.

The Kv4.3 channel on c-low threshold mechanoreceptors in DRG is a key mediator transforming tactile stimuli into nociceptive signals in chemotherapy-induced neuropathy

Acta Pharmaceutica Sinica B. 2026, 16(2): 854-878.

Oxaliplatin, a chemotherapeutic agent commonly used in colorectal cancer treatment, frequently induces chemotherapy-induced peripheral neuropathy (CIPN), with mechanical allodynia as a dose-limiting neurological complication. However, the precise pathophysiological mechanism underlying this sensory dysfunction remains inadequately elucidated. This study identifies Kv4.3 channel dysfunction in C-low threshold mechanoreceptors (C-LTMRs), a subset of tyrosine hydroxylase–positive (TH⁺) sensory neurons in the dorsal root ganglia (DRG), as the critical driver of oxaliplatin-induced mechanical allodynia. Using electrophysiological, pharmacological, and genetic approaches in mouse models, we have demonstrated that oxaliplatin selectively alters the firing pattern of C-LTMRs and enhances their excitability, particularly in response to low-intensity stimuli. This effect is mediated by Kv4.3 channel dysfunction within C-LTMRs, which underlies the pathological conversion of innocuous touch to pain. Critically, pharmacological inhibition or neuron-specific knockdown of Kv4.3 channels exacerbated mechanical allodynia, while Kv4.3 channel activation reversed neuronal hyperexcitability and alleviated oxaliplatin-induced mechanical allodynia. Thus, Kv4.3 dysfunction constitutes a core pathogenic mechanism of oxaliplatin-induced mechanical allodynia. Targeted enhancement of the Kv4.3 channel activity in C-LTMRs represents a promising precision analgesic strategy for this condition.

Clostridium perfringens alpha toxin drives pathological NETosis via immature neutrophil mobilization and functional reprogramming

Acta Pharmaceutica Sinica B. 2026, 16(2): 879-899.

Clostridium perfringens alpha toxin (CPA), a zinc-dependent phospholipase C, is a key virulence factor in gas gangrene. While its membrane-disrupting cytotoxicity is well characterized, its capacity to modulate neutrophil function and promote pathological inflammation is poorly defined. Here, we show that CPA induces neutrophil extracellular trap (NETs) formation by mobilizing and functionally reprogramming immature neutrophils. In a murine model, CPA challenge caused dose-dependent mortality and multi-organ injury, driven by a dramatic expansion of a pro-NETotic immature neutrophil subset identified by single-cell RNA sequencing. This was confirmed by elevated systemic NETs markers and extensive NETs deposition in damaged tissues. Mechanistically, CPA directly triggered reactive oxygen species (ROS)-dependent, peptidylarginine deiminase 4 (PAD4)-mediated NETosis in both murine and human neutrophils, revealing a conserved pathogenic mechanism. Importantly, therapeutic targeting of the NETotic pathway—via PAD4 inhibition, (Deoxyribonuclease I) DNase I treatment, or neutrophil depletion—significantly reduced tissue damage and improved survival. These findings identify a CPA–neutrophil–NETs axis as a central driver of immunopathology. Our study reframes CPA from a classical cytolysin to a potent immunomodulatory toxin that hijacks neutrophil fate. Our findings validate the NETotic pathway as a critical therapeutic target, providing a strong rationale for developing host-directed therapies—potentially in combination with toxin-neutralizing agents—to combat severe toxin-driven diseases.

OTUD6A drives dopaminergic neuronal degeneration of Parkinson's disease through deubiquitinating ACTG1 in neuronal cells

Acta Pharmaceutica Sinica B. 2026, 16(2): 820-835.

Parkinson's disease (PD) is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. Emerging evidence suggests that deubiquitinating enzymes (DUBs), which regulate protein homeostasis through the cleavage of ubiquitin chains, play critical roles in PD pathogenesis. In this study, we discovered that a DUB, ovarian tumor deubiquitinase 6A (OTUD6A), was significantly upregulated in both PD patients and PD mouse models. Notably, OTUD6A deficiency effectively protected dopaminergic neurons from degeneration and improved motor deficits in both acute and chronic PD mouse models. Through comprehensive mass spectrometry analysis and co-immunoprecipitation assays, we identified that actin gamma 1 (ACTG1) serves as a key substrate of OTUD6A. Mechanistically, OTUD6A specifically interacts with the 8–181 aa domain of ACTG1 and preferentially cleaves K48-linked polyubiquitin chains, thereby enhancing ACTG1 protein stability in neuronal cells. The stabilized ACTG1 subsequently binds to p53 and facilitates its nuclear translocation, leading to the transcriptional activation of pro-apoptotic genes and promoting neuronal apoptosis. Collectively, our findings demonstrate that OTUD6A promotes dopaminergic neuron degeneration and PD progression by deubiquitinating and stabilizing ACTG1, which in turn activates a p53-dependent apoptotic pathway. These findings identify OTUD6A as a potential therapeutic target for PD intervention.

Anti-influenza drugs targeting trimeric RNA polymerase complex: From development to clinics

Acta Pharmaceutica Sinica B. 2026, 16(2): 728-745.

The rapid evolution of influenza viruses, driven by high mutation rates and cross-species transmission, underscores the importance of discovering antivirals with novel mechanisms of action and distinct resistance profiles. The influenza virus RNA polymerase, a highly conserved heterotrimeric complex, comprises polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA) in influenza A and B viruses, or polymerase 3 protein (P3) in influenza C and D viruses. This complex is essential for viral genome replication and transcription, rendering it a critical target for antiviral intervention. Over the past two decades, research on influenza polymerase (FluPol) has advanced from fundamental studies to drug development and clinical application. By 2025, six FluPol-targeting drugs have received regulatory approval: the PA inhibitors baloxavir marboxil, suraxavir marboxil, seloxavir marboxil, and pixavir marboxil; the PB1 inhibitor favipiravir; and the PB2 inhibitor onradivir, with several additional candidates progressing to clinical research. This review summarizes the structure and function of influenza polymerase and the mechanisms of action of different inhibitors, highlighting the discovery and clinical effectiveness of the newly approved FluPol-targeting drugs. It addresses the potential of FluPol inhibitors against highly pathogenic avian influenza and the challenges posed by resistance mutations.

Harnessing deep learning to accelerate the development of antibodies and aptamers

Pan Tan, Song Li, Jin Huang, Ziyi Zhou, Liang Hong

Acta Pharmaceutica Sinica B. 2026, 16(2): 788-801.

Artificial intelligence (AI) has revolutionized the design of antibodies and RNA aptamers, driving significant advancements in molecular therapeutics. In antibody design, AI enables accurate structure prediction and optimization of binding affinity, specificity, and stability, thereby accelerating the development of therapies targeting challenging antigens, such as those associated with viral infections and cancer. By integrating sequence and structural data, AI significantly reduces experimental costs and development timelines, streamlining the creation of next-generation antibody-based therapeutics. Similarly, AI has transformed RNA aptamer design, addressing long-standing challenges in structure prediction and binding optimization. AI-driven approaches allow for the rapid generation of aptamers with enhanced specificity, stability, and functional properties, expanding their potential applications in both therapeutics and diagnostics. These advancements offer scalable, cost-effective, and highly customizable solutions for precision medicine. As AI systems continue to evolve and integrate with experimental validation, they hold immense promise for developing more effective treatments for complex diseases, including cancer, autoimmune disorders, and viral infections. This marks the beginning of a new era in therapeutic innovation, where AI plays a pivotal role in addressing the challenges of modern medicine.

Gut microbiota drives the metabolic dysregulation in obesity-prone individuals by impairing GDCA-mediated activation of brown adipose thermogenesis and ileal GLP-1 secretion

Han Ma, Yuqi Wu, Delong Li, Haowen Sun, Yuan Xie, Shichun Zhao, Wenqian Guo, Meng Wang, Renyun Cui, Yanrong Huang, Xiankang Zhang, Jin-Yi Wan, Haiqiang Yao, Chun-Su Yuan

Acta Pharmaceutica Sinica B. 2026, 16(2): 836-853.

Obesity-prone (OP) individuals exhibit an intrinsic predisposition to obesity and associated metabolic disorders, and early intervention in this population holds significant clinical value; however, the underlying mechanisms driving this susceptibility remain largely obscure. This study enrolled 46 OP subjects without diagnosed metabolic diseases and 35 healthy controls. Our findings revealed that, despite not reaching obesity diagnoses, OP subjects exhibited significant metabolic disturbances strongly associated with gut microbiota dysbiosis. They also displayed disturbed bile acid (BA) profiles, with depleted glycodeoxycholic acid (GDCA) identified as the most potent discriminator between the OP and healthy controls. Fecal microbiota transplantation (FMT) recapitulated metabolic dysfunction and BA pool remodeling, mediated by dysregulated hepatic expression of BA synthesis genes of Cyp8a1, Cyp7a1, and Cyp7b1. Notably, FMT-OP mice also phenocopied the diminished GDCA levels observed in OP subjects. GDCA supplementation in obese mice markedly improved body weight, hepatic steatosis, and metabolic dysfunction. Mechanistically, GDCA exerted anti-obesity effects by activating the TGR5 signaling, which enhanced brown adipose tissue (BAT) thermogenesis and stimulated ileal glucagon-like peptide-1 (GLP-1) secretion, thereby ameliorating obesity and associated metabolic dysregulation. Thus, these findings indicate that gut microbiota-driven dysregulation of BA signaling, particularly impaired TGR5 activation due to diminished GDCA, underlies glycolipid metabolic dysfunction in OP individuals.