Acta Pharmaceutica Sinica B

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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.
A novel fusion protein of COVID-19 virus enhancing protection of Syrian hamsters infected with SARS-CoV-2

Acta Pharmaceutica Sinica B. 2026, 16(2): 900-912.

COVID-19 and its variants have spread around the world, triggering a range of long-term sequelae and leading to the need for broadly effective vaccines. We have established a new fusion protein combining the receptor-binding domain region (SF2) and a newly identified conserved binding region (SF5) from the spike of SARS-CoV-2. This fusion protein (COVID19-SF2+SF5) specifically bound to VERO-E6 cells with higher efficiency than either region alone. Antibodies raised in mice against COVID19-SF2+SF5 cross-reacted with every fragment of SARS-CoV-2 and SARS. Additionally, antibodies against the fusion protein effectively neutralize pseudoviruses of both wild-type and mutant strains of SARS-CoV-2 (including BA.3, XBB.1.5, and EG.5), as well as SARS pseudoviruses. Protein interaction prediction and binding affinity determination revealed that the fusion protein exhibits strong binding capacity to three key host molecules: heparan sulfate proteoglycan (HSPG), neuropilin-1 (NRP1), and cluster of differentiation 147 (CD147). Analysis of representative viruses from four coronavirus genera (α, β, γ, δ)—including 229E, NL63, OC43, HKU1, SARS-CoV, MERS-CoV, HKU20, and IBV—revealed that these coronaviruses share sequence similarity mainly on SF2 and SF5 regions. Furthermore, immunization of female hamsters with COVID19-SF2+SF5 provided significant protection against a SARS-CoV-2 virus challenge. Taken together, our results indicate that vaccination with a protein containing both an receptor binding domain (RBD) region and a common binding region provides strong protection during infection, thus suggesting a potential strategy to avoid evasion of host immune recognition by virus variants. Significantly, the observation that COVID19-SF2+SF5 immunization possesses stronger activity in reducing viral load at early stages suggests that the SF5 region might play an important role in virus recognition and binding to host cells. Based on these findings, we conclude that it is possible to develop universal vaccines and neutralizing monoclonal antibodies to curb the effects of mutations and to target multiple coronaviruses.
Blocking TRIM47-mediated HNF4α degradation suppresses hepatocellular carcinoma progression

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.
Cold exposure-induced β-hydroxybutyrate promotes brown fat mitochondrial lipid droplet contact to ameliorate fatty dysfunction and hepatic steatosis

Acta Pharmaceutica Sinica B. 2026, 16(2): 930-947.

Cold exposure activates brown adipose tissue (BAT), to alleviate metabolic disorders. However, the mechanisms underlying the regulation of mitochondrial lipid droplet contact (MLC) in BAT and their association with these benefits remain unclear. Here, we identify liver-derived β-hydroxybutyrate (BHB) as a key mediator in driving MLC formation in BAT. Mechanistically, BHB directly targets at the GLY-67 residue of RAB10, enhancing its interaction with PLIN5 to form the RAB10–PLIN5 complex, which facilitates MLC. This interaction was validated using SPIDER and biotin-labeled pull-down assays. Functionally, BHB treatment reduces lipotoxicity and improves metabolic health in diet-induced obese mice. These findings establish BHB as a critical link between BAT MLC and the systemic metabolic benefits, highlighting the RAB10–PLIN5 complex as a therapeutic target for obesity and hepatic steatosis. Furthermore, this work underscores the broader significance of cold-induced metabolic adaptations for combating metabolic diseases.
REEP6 promotes colorectal cancer glycolysis and tumorigenesis through PRMT5-mediated PGAM1 arginine methylation

Tuo Wang, Dongsheng Zhang, Chi Jin, Hengjie Xu, Hongxu Nie, Ye Wang, Chuan Zhang, Yifei Feng, Junwei Tang, Yueming Sun

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.
Complete biosynthesis of phenylspirodrimanes with unclustered genes in Stachybotrys chartarum

Acta Pharmaceutica Sinica B. 2026, 16(2): 966-978.

Phenylspirodrimanes are a class of structurally diverse meroterpenoids, including the bioactive dimer stachybocin A (1) and the high-reactivity monomer stachybotrydial (2), which are isolated from the genus Stachybotrys. Whereas the biosynthetic pathway of these phenylspirodrimane meroterpenoids has remained elusive. Herein, we deciphered the complete biosynthetic pathway of 2 with unprecedented two gene clusters and five discrete genes by genome mining, gene inactivation, heterologous expression, biochemical experiments, and especially combining with transcriptome-based hierarchical clustering and expression correlation analyses. Totally, 11 genes for the phenylspirodrimane core skeleton formation, 8′-methyl oxidation, and 3-OH epimerization were efficiently discovered and functionally characterized. Notably, these biosynthetic genes are distributed across seven distinct regions, with a rare combination of multiple gene clusters and genes outside the clusters. Bioactivity assays revealed that four intermediates 6-8, and 9a exhibited significant inhibitory effect on the inactivated state hNaV1.2 channels with IC₅₀ values of 0.15, 0.04, 0.28, and 1.91 μmol/L, respectively. These findings expand our understanding of phenylspirodrimane-type meroterpenoid biosynthesis and underscore the utility of transcriptome-based hierarchical clustering and expression correlation analyses for identifying unclustered biosynthetic genes in fungi.
Targeting oncogenic K-RAS mutants with small-molecule degrader XMU-MP-9 through NEDD4-1

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.
Carboxylated prodrug of capsaicin with enhanced peripheral nerve permeation mediated by monocarboxylate transporters for long-lasting local anesthesia

Yu Wen, Tian Yang, Qi Li, Xiaosi Li, Xiaoyan Ma, Huiyang Hu, Prabhakar Busa, Sayma Alam, Libo Tan, Chao Zhao

Acta Pharmaceutica Sinica B. 2026, 16(2): 994-1008.

Perineurally injected nerve-blocking agents have limited capability to cross peripheral nerve barriers (PNBs), requiring high doses to block pain signals on axons. This increases the risk of local tissue toxicity and systemic side effects on the cardiovascular and neurological systems. To address this, we explored carboxyl group modification to enhance the permeability of nerve-blocking agents across the PNBs through carrier-mediated transport facilitated by monocarboxylate transporters (MCTs). The enhanced permeability allows for targeted drug delivery to peripheral nerve axons, resulting in a significant reduction in the necessary drug dosage for a long-lasting nerve block. Specifically, we developed a carboxylated prodrug of capsaicin (COOH-CAP) by conjugating it with a carboxyl group via a degradable ester bond. Calcium flux assays, patch-clamp recordings, and body temperature measurements collectively confirmed that COOH-CAP activates TRPV1, with potency comparable to capsaicin. In rats, a single sciatic nerve injection of 3.28 μmol COOH-CAP produced a nociceptive-selective nerve blockade lasting 260 ± 83.7 h without motor impairment or capsaicin-related side effects, approximately 35 times longer than the same dose of plain capsaicin. Even at a lower dose of 1.64 μmol, COOH-CAP still produced nociceptive-selective nerve blockade for 172.0 ± 41.3 h.
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.
Multifunctional extracellular vesicles inhibiting autophagy ameliorate immunotherapy in non-small cell lung cancer

Simiao Wang, Jiayi Chen, Yaxin Cui, Jianming Xing, Jiayi Liu, Hao Jiang, Hongqun Yang, Huan Zhang, Man Sun, Jialin Li, Wei Liu, Zhou Chen, Wei Sun, Xiaobing Wang, Zhaogang Yang

Acta Pharmaceutica Sinica B. 2026, 16(2): 1022-1045.

The modulation of tumor autophagy to enhance antitumor immunity has garnered significant attention, underscoring its critical role in cancer immunotherapy. However, advanced strategies for precise autophagy-regulating drug delivery remain a pressing need. Here, we introduce a targeted small extracellular vesicles (sEVs)-based drug delivery system capable of simultaneously loading antibodies and nucleic acid drugs while ensuring their accurate release in the tumor microenvironment (TME). We developed a dual-stimulation electroporation system that integrates nanosecond electric pulses and ultrasound to enhance sEV production, yielding IL-7 mRNA-enriched sEVs that overexpress CD64 receptors for efficient capture of anti-PD-L1 antibodies. These multifunctional autophagy-inhibiting and immunomodulatory sEVs (AI-sEVs) are designed to inhibit autophagy and modulate immune responses in non-small cell lung cancer. Upon delivery to the TME, AI-sEVs mediate the enzymatic cleavage of peptide bonds, releasing IL-7 mRNA. This process induces autophagy suppression and restores MHC-I expression, which synergizes with anti-PD-L1 immune checkpoint inhibition to enhance antitumor efficacy. In conclusion, this study proposes an innovative methodology that utilizes engineered sEVs for the co-delivery of protein antibodies and genetic materials. This approach establishes a promising strategy for advancing cancer immunotherapy by targeting the modulation of autophagy.

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