Acta Pharmaceutica Sinica B

A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function

Acta Pharmaceutica Sinica B. 2026, 16(4): 2396-2419.

Pepducins are synthetic membrane-tethered lipopeptides designed to allosterically modulate G protein-coupled receptor (GPCR) signaling. Here, we characterize a series of pepducins targeting the neurotensin receptor type 1 (NTSR1), revealing their complex and multifaceted modulation properties. Using BRET-based biosensors, we show that PP-001, a pepducin derived from NTSR1’s first intracellular loop, preferentially activates G protein over β-arrestin signaling while inhibiting NT binding, NT-induced β-arrestin recruitment, and NTSR1 internalization, thereby acting as biased allosteric agonist and negative allosteric modulator. PP-001 also promotes the formation of both homo- and heteromeric multi-receptor complexes. In vivo, PP-001 elicits potent, sustained hypotensive effects, reversible by the NTSR1 antagonist SR48692. Although the precise mechanism of pepducin-receptor interaction remains unclear, we identify a critical N-terminal RKK motif for PP-001’s biological activity. Finally, thermodenaturation assays using purified NTSR1, combined with mutagenesis and molecular docking, provide evidence for the role of the receptor’s H8 domain in direct pepducin interaction. Together, these findings highlight pepducins as versatile modulators of GPCR function and as valuable pharmacological tools for GPCR-targeted drug development.

Engineered bacteria reprogram tumor microenvironment via cell senescence and neutrophil extracellular traps degradation

Wanfa Dong, Chenyang Li, Jiqiang Lu, Lin Weng, Yicong Xu, Min Xu, Peiqi Li, Yanhui Wu, Zixuan Shan, Pengyou Shang, Liangliang Dai, Tao Zhang, Yanlong Jia, Tianyun Wang, Wenjie Ren, Ping Lu, Xiao Chen, Zichun Hua

Acta Pharmaceutica Sinica B. 2026, 16(4): 2332-2356.

Attenuated Salmonella VNP20009 (VNP) shows promising anti-cancer therapeutic potential. Limited understanding of its anti-tumor mechanism has hindered broader clinical application. Recent studies have reported cellular senescence is involved in tumor progression; however, its critical role in VNP therapy remains elusive. Our study revealed that VNP exerts anti-tumor growth and anti-angiogenesis effects by inducing cellular senescence in tumor cells and vascular endothelial cells. While VNP-induced senescence inhibits tumor growth, it concurrently promotes neutrophil extracellular traps (NETs), which paradoxically enhance tumor progression. To address this challenge, we engineered VNP-SNase, a novel variant capable of releasing the DNA-degrading enzyme Staphylococcus aureus nuclease directly within tumors. VNP-SNase significantly inhibited NETs formation across multiple tumor types, effectively promoted anti-tumor immunity, and exhibited improved tumor suppression effects with enhanced biosafety. Our findings elucidate the critical role of cellular senescence in VNP therapy and propose targeting NETs as a strategic approach to enhance the efficacy of VNP-based cancer treatments.

Generative active learning guided discovery of a tobramycin and ciprofloxacin adjuvant against multidrug-resistant Pseudomonas aeruginosa infections

Siyu Zhao, Jie Tang, Ziyang Du, Yujie Li, Yingbo Zhou, Wenqian Liu, Xiao Wu, Xibing Hu, Xin Long, Dengchao Lian, Jinglin Xie, Tiantian Xie, Shuo Dai, Daxi He, Jiahui Su, Youfeng Zhu, Yiqun Chang, Junxia Zheng, Jun Liu, Pinghua Sun

Acta Pharmaceutica Sinica B. 2026, 16(4): 2444-2473.

Biofilm-mediated resistance in multidrug-resistant (MDR) Pseudomonas aeruginosa infections severely compromise antibiotic efficacy in clinical applications. Antibacterial adjuvants represent a promising strategy to restore antibiotic sensitivity and reduce therapeutic dosages. To identify new antibacterial adjuvants with unique structure and mechanism, we established a generative active learning workflow integrating an in-house compound repository of 725 biofilm inhibitors and a library of potential antibiofilm targets. The most potent compound STY17 was identified with sub-micromolar antibiofilm activity (IC₅₀ = 0.29 ± 0.01 μmol/L). In clinically isolated MDR Pseudomonas aeruginosa, STY17 significantly inhibited biofilm formation, potently synergized with tobramycin and ciprofloxacin, and suppressed the resistance development of these antibiotics. Furthermore, mechanistic studies indicated that STY17 inhibited succinate dehydrogenase to disrupt biofilm formation. In vivo, STY17 significantly enhanced the antibacterial activity of tobramycin and ciprofloxacin in Galleria mellonella and the mouse wound infection model with favorable safety profiles. These findings validated the utility of machine learning to discover novel antibacterial adjuvants, revealing STY17 as a promising candidate for antibacterial adjuvants against MDR Pseudomonas aeruginosa infections.

Isoalantolactone induces AML pyroptosis and potentiates α-PD-1 efficacy by targeting selenoprotein TXNRD1

Xiaoxuan Yu, Yanyu Zhou, Shibo Sun, Lu Tang, Wan Zhang, Jianqiang Xu, Wukun Liu

Acta Pharmaceutica Sinica B. 2026, 16(4): 2317-2331.

The suppressive microenvironment of AML limits anti-PD-1 efficacy, making pyroptosis induction a key strategy for its remodeling. Isoalantolactone (IAL), a naturally occurring small molecule, has been identified herein to inhibit cytosolic thioredoxin reductase1 (TXNRD1) and trigger pyroptosis in AML cells, thereby enhancing the efficacy of anti-PD-1 antibody therapy. Mechanistically, the α,β-unsaturated carbonyl group of IAL covalently bound to the selenocysteine residue at the position 498 (Sec⁴⁹⁸) of TXNRD1 through a Michael addition reaction. Clinical sample analysis revealed that TXNRD1 is overexpressed in AML, which correlates with poor prognosis. Additionally, we found that the TXNRD inhibitor auranofin has demonstrated good efficacy against AML. The inhibition of TXNRD1 activates the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), which, in turn, upregulates the transcription of caspase-3, subsequently increasing the cleavage of gasdermin E to induce pyroptosis via the non-classical pathway in AML cells. Additionally, enhanced caspase-3 activity promotes poly ADP-ribose polymerase 1 (PARP-1) cleavage and upregulates PD-L1 expression, thereby increasing sensitivity to anti-PD-1 monoclonal antibodies. Overall, the current study highlights a promising approach for augmenting therapy using anti-PD-1 monoclonal antibodies in AML by targeting TXNRD1 to induce pyroptosis and ameliorate the immunosuppressive microenvironment.

A highly promising new avenue for targeting K-RAS: The small-molecule degrader XMU-MP-9

Jian Jin

Acta Pharmaceutica Sinica B. 2026, 16(2): 1166-1167.

Rapid in vivo release of paclitaxel from polymeric micelles

Haisheng He, Jianping Qi, Yi Lu, Wei Wu

Acta Pharmaceutica Sinica B. 2026, 16(2): 1155-1165.

Profiling in vivo release kinetics of drug nanocarriers is of high translational significance. However, this has remained unrealized due to the lack of direct methodologies to quantify either the total released or residual drugs. This study employed an indirect strategy, comparing pharmacokinetics and particokinetics, to estimate the in vivo release kinetics of paclitaxel (PTX) from intravenously administered mPEG-PDLLA polymeric micelles (PMs). Blood pharmacokinetics were profiled by chromatographically quantifying PTX, while particokinetics were determined following labeling PM particles by near-infrared fluorophores with aggregation-caused quenching properties. By monitoring the dynamic change in the PTX-to-copolymer ratio, the in vivo release of PTX from the PMs was estimated. The results revealed surprisingly rapid release, with over 88.2% and 99.0% of PTX released by 15 s and 5 min post-administration, respectively. It is concluded that PTX is released rapidly from PMs in vivo, and PMs may merely work as “solvents” to solubilize PTX rather than as carriers for targeted delivery.

A new paradigm for treating lung cancer by targeting the intratumoral microbiome

Wei Wei

Acta Pharmaceutica Sinica B. 2026, 16(2): 1168-1169.

Skin-penetrating peptides derived from computational simulation improve transdermal absorption and facilitate topical treatment of melanoma

Acta Pharmaceutica Sinica B. 2026, 16(2): 1140-1154.

Transdermal drug delivery relies heavily on the skin permeability of therapeutic agents. In order to develop a peptide-based delivery strategy for promoting transdermal absorption, the key physicochemical factors influencing skin permeability are first identified through cell-penetrating peptides (CPPs) screening and computational simulation. Penetratin exhibits the most outstanding permeability and safety among CPPs from various origins, and positive surface patch area emerges as the key property correlated with skin permeability of the peptides. Based on these findings, a precise model to predict skin permeability of the peptides is established, leading to the computational redesign of penetratin’s amino acid sequence. The transdermal delivery efficiency of optimized penetratin derivative (589WP) is significantly improved in vitro compared with wild-type penetratin and visualized through in vivo imaging. Furthermore, the anti-metabolic drug floxuridine (FUdR) is covalently conjugated with 589WP via ester linkage, leading to accelerated FUdR release due to esterase degradation. Subsequently, this conjugate is formulated into an anhydrous gel, which significantly inhibits melanoma growth with topical application, outperforming a higher dose of free FUdR without observed skin irritancy or toxicity. The peptide prediction and design approaches established herein hold great potential for advancing transdermal drug delivery.

Author correction to “A high clinically translatable strategy to anti-aging using hyaluronic acid and silk fibroin co-crosslinked hydrogels as dermal regenerative fillers” [Acta Pharmaceutica Sinica B 15 (2025) 3767–3787]

Jialing Cheng, Zhiyang Chen, Demin Lin, Yanfang Yang, Yanjing Bai, Lingshuang Wang, Jie Li, Yuchen Wang, Hongliang Wang, Youbai Chen, Jun Ye, Yuling Liu

Acta Pharmaceutica Sinica B. 2026, 16(2): 1170-1172.

Author correction to “Cerium single-atom catalysts-armed Lactobacillus reuteri for multipronged anti-inflammatory/anti-fibrotic therapy of inflammatory bowel disease” [Acta Pharmaceutica Sinica B 15 (2025) 5400-5415]

Acta Pharmaceutica Sinica B. 2026, 16(2): 1173-1174.