Acta Pharmaceutica Sinica B

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Agonist-specific FPR1 conformational change prevents receptor recycling and promotes targeted protein degradation

Acta Pharmaceutica Sinica B. 2026, 16(5): 3043-3058.

Recycling of internalized cell surface receptors is critical for membrane transport and receptor-mediated signaling. Formyl peptide receptor 1 (FPR1) plays important roles in host defense and inflammatory tissue injury. Here we report that fMet-Leu-Phe-Cys (fMLFC), a peptide agonist of FPR1, prevents recycling of internalized FPR1 and diverts it to the late endosome and lysosome for degradation. In contrast, FPR1 bound to the classic ligand fMLF interacts with RAB11 and SNX17, facilitating its recycling back to the cell surface. We determined a cryo-EM structure of fMLFC-bound FPR1-Gi complex. Alanine substitutions of key residues that interact with fMLFC (F102A, T177A, F178A) improved FPR1 recycling. Using a FlAsH-NanoBRET-based FPR1 biosensor, the fMLFC-induced receptor conformational change was found to be different from the fMLF-induced conformational change. fMLFC stimulation reduced FPR1 cell surface expression, along with reduced acute lung injury in LPS-treated mice. Our findings suggest that fMLFC is a chemical knockdown agent that promotes targeted protein degradation and reduces FPR1-mediated inflammation.
Red blood cell damage defines the etiology of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids

Acta Pharmaceutica Sinica B. 2026, 16(5): 3059-3073.

Hepatic sinusoidal obstruction syndrome (HSOS), a life-threatening liver disease characterized by sinusoidal endothelial cell (LSEC) damage, is frequently caused by pyrrolizidine alkaloid (PA) exposure present in numerous herb or food products. Unlike other hepatotoxins, the precise mechanism by which PAs selectively target LSECs remains poorly understood, posing significant challenges to the development of effective treatments. This study identified hemolysis as the initiating event in PA-HSOS pathogenesis through clinical and animal model analyses. PA exposure induced red blood cell (RBC) rupture, releasing free hemoglobin (Hb) that directly damaged LSECs. Mechanistic investigations revealed that PA-formed protein adducts with haptoglobin (Hp), impairing its protective effect against toxic Hb and triggering a cascade of LSEC activation, ferroptosis, and hemorrhagic liver necrosis. Rescue study revealed that Hp supplementation effectively mitigated PA-induced liver injury by scavenging free Hb. Clinical validation demonstrated elevated Hb-Hp adducts and cell-free Hb in PA-HSOS patients, confirming concordant intoxication mechanisms across species. The findings redefine PA-HSOS as a hematogenous liver disorder originating from RBC destabilization, rather than direct hepatocyte toxicity. This hematopathological perspective reveals Hp replacement therapy as a promising etiological treatment strategy, addressing the root cause rather than secondary liver damage.
Targeting cancer-associated fibroblast-activated HGF/c-MET pathway inhibits extrahepatic cholangiocarcinoma progression and restores gemcitabine therapeutic sensitivity

Mingzhen Bai, Ping Yue, Wenkang Fu, Ruyang Zhong, Chongfei Huang, Ningzu Jiang, Long Gao, Ningning Mi, Haidong Ma, Yawen Lu, Liang Tian, Jinyu Zhao, Ziang Zhang, Yong Zhang, Jinduo Zhang, Yanxian Ren, Haiying Yu, Jia Yao, Dewei Li, Yanyan Lin, Wenbo Meng

Acta Pharmaceutica Sinica B. 2026, 16(5): 3074-3089.

Cholangiocarcinoma (CCA) is a markedly desmoplastic tumor, with extrahepatic CCA (eCCA) being the most prevalent subtype. The nonspecific clinical manifestation and early metastatic potential result in a persistently poor overall prognosis. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor microenvironment implicated in tumor progression and treatment resistance. To faithfully recapitulate the eCCA microenvironment, we established a comprehensive patient-derived preclinical platform comprising CAFs, eCCA primary cells, organoids, and patient-derived xenograft (PDX) models. We found that CAFs facilitated eCCA cell growth, migration, and invasion in vivo and in vitro. Cytokine profiling revealed that HGF is a key paracrine factor produced by CAFs. CAF-derived HGF activates c-MET signaling to drive gemcitabine resistance in eCCA. Therapeutically, pharmacologic inhibition of c-MET partially resensitized eCCA cells to gemcitabine in preclinical models and suppressed tumor progression. In conclusion, our data provides subtype-specific translational evidence that therapeutically targeting the CAF-HGF-c-MET pathway represents a rational strategy to enhance gemcitabine efficacy and improve treatment outcomes in eCCA.
Targeting SCAMP2 by a natural product auxarconjugatin B for glioblastoma therapy via restoring aspartate metabolic flux

Acta Pharmaceutica Sinica B. 2026, 16(5): 3090-3108.

Glioblastoma (GBM), the most aggressive primary brain malignancy, presents an urgent need for novel therapeutic targets addressing metabolic reprogramming in tumor progression. Natural product-based molecular probes have emerged as powerful tools for target discovery and mechanistic elucidation in cancer biology. Here, we identified the fungal polyketide auxarconjugatin B (AUX-B) as a potent inhibitor of GBM proliferation through both in vitro and in vivo models. Chemical biology strategies revealed secretory carrier membrane protein 2 (SCAMP2) as the covalent cellular target of AUX-B. SCAMP2 exhibited significant overexpression in human GBM specimens and orthotopic GBM mouse models, correlating with tumor progression. Mechanistic investigations demonstrated that SCAMP2 orchestrates metabolic reprogramming through the regulation of aspartate transporters (solute carrier family 1 member 3 and solute carrier family 25 member 12) and asparagine synthetase, thereby sustaining aspartate metabolic flux critical for GBM growth. AUX-B-mediated reduction of SCAMP2 effectively disrupted this pathogenic metabolic network, leading to a decrease in intracellular aspartate levels. Our findings establish SCAMP2 as a novel therapeutic target in GBM and characterize AUX-B as a new SCAMP2 inhibitor with translational potential through metabolic modulation.
A new approach to discovering a broad-spectrum anti-respiratory virus drug: Tubeimoside II modulates host factor PACT to potentiate the RIG-I antiviral pathway

Acta Pharmaceutica Sinica B. 2026, 16(5): 3109-3127.

PACT (PKR activating protein)/PRKRA is a quintessential double-stranded RNA (dsRNA) binding protein that has recently surfaced as a novel and compelling antiviral target, exhibiting resistance against a spectrum of respiratory viruses. Despite this, no antiviral ligand compounds targeting PACT have been identified to date. In this study, we conducted an extensive screening within natural products, leading to the development of an exceptional PACT-T78 site ligand, tubeimoside II (TBM II). TBM II effectively combats a spectrum of respiratory viruses, including the coronaviruses HCoV-OC43 and SARS-CoV-2, as well as the influenza A H1N1 virus (IAV-H1N1), by reducing viral loads and inhibiting viral replication and proliferation both in vitro and in vivo. Single-cell RNA sequencing demonstrated that TBM II significantly impacts the RIG-I signaling pathway associated with PACT. We found that when PACT was knocked down or when RIG-I, MAVS, or IFN-β were knocked out, the ability of TBM II to activate the RIG-I signaling pathway was diminished, resulting in a corresponding attenuation of its antiviral efficacy. These findings indicated that TBM II targets PACT to activate the RIG-I signaling pathway, thereby increasing the secretion of type I interferon IFN-β, ultimately promoting the innate immune response and achieving antiviral efficacy. In summary, our work identified TBM II as a new generation PACT ligand that activating the RIG-I signaling pathway, achieving broad-spectrum antiviral effects.
Identification of boholamide A analogue as a potential hypoxia-selective anti-triple-negative breast cancer agent by targeting eEF1A1

Acta Pharmaceutica Sinica B. 2026, 16(5): 3128-3156.

Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic forms of breast cancer, for which there are currently no satisfactory therapeutic agents. Here, we reported for the first time that boholamide A, a naturally occurring macrocyclic depsipeptide, exhibited hypoxia-selective anti-TNBC activity against in MDA-MB-231 cells. However, its structure-activity relationships and target had not yet been elucidated. A series of boholamide A analogues were chemically synthesized and evaluated for anti-TNBC potency. The most promising compound 1j was prepared in 13 linear steps with an overall yield of 7.92%, and exhibited high potency against MDA-MB-231 cells with an IC₅₀ value of 0.15 μmol/L under hypoxic condition. Moreover, 1j significantly inhibited proliferation and migration, and induced apoptosis in MDA-MB-231 cells. Compound 16, a prodrug of 1j, significantly inhibited the tumor volume and tumor weight in xenografts. Furthermore, we identified that 1j covalently targeted eukaryotic translation elongation factor 1alpha 1 (eEF1A1) which might underlie the anticancer activity and hypoxia selectivity of boholamide A analogues. These results suggested that boholamide A analogues represented a promising scaffold for discovering hypoxia-selective anti-TNBC agents, and compound 16 deserved further investigation as a candidate for TNBC treatment.
A novel entry inhibitor targeting the stalk domain of the hemagglutinin of H1N1

Ying Gong, Tongyu Bi, Fuling Xiao, Dandan Xu, Xun Zhang, Han Wang, Peng Yu, Xiaoqian Yang, Jianping Zuo, Li Yang, Weibo Yang, Xiankun Tong

Acta Pharmaceutica Sinica B. 2026, 16(5): 3157-3174.

Influenza is a global health issue. Vaccines can protect humans from infection from influenza virus. When no suitable vaccine is available, anti-influenza drugs are the first treatment choice. Emergence of drug resistance necessitates development of novel anti-influenza virus drugs. We investigated a novel macrocyclic compound H1N1-17 using in vitro assays. Through evaluation of its antiviral effect against H1N1 and H3N2 viruses, compound H1N1-17 showed selective inhibition of H1N1 virus strains. Invasion of pseudo-H1N1 was blocked by H1N1-17 in the entry inhibition assay. Membrane fusion of H1N1 and the endosome mediated by the stalk domain of hemagglutinin was inhibited by H1N1-17. In the induction of a drug-resistant mutations assay, the resistant sites of H1N1 to H1N1-17 were located in the F subdomain of hemagglutinin, which is crucial for membrane fusion. Intraperitoneal administration of compound H1N1-17 protected mice challenged with lethal H1N1 from death and weight loss, and effectively alleviated lung injury caused by viral infection. Additionally, compound H1N1-17 exhibited synergistic anti-influenza activity with oseltamivir acid, which was of significance for combination therapy.
Inhalational therapy of pulmonary infection via macrophage-targeted nanoemulsions

Hairui Wang, Jinghong Xian, Guonian Zhu, Zhiqiang Xie, Guangsheng Du, Yongshun Zhang, Lan Yang, Yunming Zhang, Teng Li, Yehui Zhou, Weimin Li, Xun Sun, Chengdi Wang

Acta Pharmaceutica Sinica B. 2026, 16(5): 3175-3190.

The dynamic immune landscape within the tuberculous (TB) granuloma microenvironment critically governs antibiotic penetration efficiency, bacterial persistence, and long-term therapeutic outcomes. Herein, we present a macrophage-targeted inhalable nanoemulsion for co-delivering rifampicin and LCL161, an inhibitor of apoptosis protein antagonist. Inhaled mannose-nanoemulsions (named RL-NE@Man) enable granuloma-targeted delivery in TB mice model, increasing infected macrophage apoptosis, remodeling the tuberculosis microenvironment, and promoting T-cell immunity to synergize with antibiotics for the eradication of granulomas and persistent Mycobacterium tuberculosis infection. Following two-dose inhalational administration, RL-NE@Man displayed potent bactericidal activity against M. tuberculosis while concurrently alleviating pulmonary pathological lesions and hyperinflammatory responses, demonstrating superior bacterial suppression efficacy compared with that of the first-line rifampicin monotherapy. This inhaled combination therapy, which integrates immunomodulators with antibiotics to modulate the local immune landscape and synergistically enhance bactericidal efficacy, represents a novel therapeutic strategy for precision tuberculosis management.
Trojan horse-inspired smart single-atom nanozyme delivery system for synergistic therapy of inflammatory bowel disease

Acta Pharmaceutica Sinica B. 2026, 16(5): 3191-3210.

Systemic administration for the clinical management of inflammatory bowel disease (IBD) often leads to various side effects and toxicities, primarily due to broad therapeutic exposure of non-target tissues. Herein, a smart single-atom nanozyme (SAzymes) delivery system (Fe-SA/Cur@HAD, FCH) is constructed through coordinating iron-doped SAzymes (Fe-SA) with curcumin (Cur) for IBD synergistic therapy. Inspired by Trojan horse, FCH efficiently responds to the IBD pathological microenvironment and realizes targeted delivery via oral administration. In inflamed colonic tissue, FCH regulates redox homeostasis through the superoxide dismutase (SOD)-catalase (CAT) cascade reaction and releases Cur by changing the adsorption energy, thus achieving synergistic therapy. An in vitro IBD model of human-derived colonic organoid, along with in vivo IBD model of mouse, were used and demonstrated that this system could effectively reduce reactive oxygen species (ROS) levels, improve intestinal homeostasis, and promote tissue recovery. Additionally, FCH markedly suppresses the activation of inflammatory pathways and modulates the composition of the intestinal microbiota. This study innovatively modifies SAzymes, offering new perspectives on their potential applications in IBD treatment.
Multistage responsive microneedle delivery system loaded oncolytic virus for topical therapy of melanoma

Zhongjie Wang, Zewei Yan, Hanlin Chen, Yue Wang, Yingjie Shi, Yuantian Jing, Ruiqi Ming, Shujun Liu, Pengfei Jin, Guanghao Wu, Lili Huang

Acta Pharmaceutica Sinica B. 2026, 16(5): 3211-3223.

Melanoma, the most aggressive form of skin cancer, remains a formidable therapeutic challenge. While oncolytic viruses (OVs) exhibit promising antitumor potential, their efficacy is often limited by insufficient intratumoral viral replication, poor tissue penetration, and the immunosuppressive tumor microenvironment (TME). Herein, a multistage microneedle (MN-OJ) system designed to amplify both local oncolysis and systemic antitumor immunity mediated by oncolytic adenovirus (OA) in melanoma. The dissolvable MN base facilitates rapid OA delivery, inducing tumor cell lysis and subsequent release of tumor-associated antigens to prime T-cell responses. Concurrently, the degradable MN tip enables sustained release of JQ1, which enhances OA replication, modulates lactic acid levels and PD-L1 expression, thereby reprogramming the immunosuppressive TME to promote T-cell infiltration and cytotoxicity. In murine models, MN-OJ demonstrated potent inhibition of both primary and distal tumors, without systemic toxicity. This innovative platform combines immediate tumor destruction with sustained immune modulation, offering a promising clinical approach for melanoma therapy.

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