Acta Pharmaceutica Sinica B

Liposomal simvastatin potentiates intranasal H1N1 influenza subunit vaccine via increasing transcytosis of antigen and submucosal dendritic cell recruitment

Acta Pharmaceutica Sinica B. 2026, 16(3): 1625-1642.

Intranasal vaccines specifically eliciting mucosal immunity in the upper respiratory tract have shown advantages in protecting against respiratory virus invasion. Yet, no clinically licensed intranasal adjuvant remains a major hurdle for the development of intranasal vaccines with low immunogenic antigens like subunit vaccines. Here, we show that liposomes loading simvastatin (Lipo-SV) serve as potent mucosal adjuvants for the intranasal liposomal subunit vaccine encapsulating the hemagglutinin 1 (HA1) glycoprotein of A/PR/8/34 (PR8) H1N1 influenza (Lipo-HA1), providing robust protection against the lethal PR8 H1N1 infection. Compared to cholera toxin subunit B (CTB), the only mucosal adjuvant used in humans, the Lipo-SV substantiate intranasal Lipo-HA1 vaccines to elicit robust systemic and local mucosal immune responses. The underlying mechanism of the adjuvanticity of Lipo-SV involves the increased transcytosis of antigens by inhibiting the geranylgeranylation of RAB5 and RAB7B GTPases in nasal epithelial cells. Moreover, Lipo-SV enhance the submucosal recruitment of dendritic cell for antigen uptake via the Toll-like receptor 4-dependent pathway. Unlike CTB, intranasal Lipo-SV do not induce inflammation in the lung or the inflammatory cytokines in the central nervous system. Our results present a paradigm of design of mucosal adjuvant to target the mucosal epithelial cells in addition to the antigen-presenting cells.

Multi-omics-based identification of METTL11B as a novel biomarker in esophageal squamous cell carcinoma

Acta Pharmaceutica Sinica B. 2026, 16(3): 1773-1778.

Inhibition of PGK1 enhances sensitivity to tyrosine kinase inhibitor in T315I-mutant leukemia

Huijing Wang, Fengyu Jiang, An Pan, Chenlong Jin, Yangyang Xue, Wenjie Liu, Renjun Gu, Yanyu Zhou, Qiuhong Shen, Tonghui Ma, Xiaoxuan Yu

Acta Pharmaceutica Sinica B. 2026, 16(3): 1449-1465.

Phosphoglycerate kinase 1 (PGK1) is traditionally recognized for its pivotal role in glycolysis. Our findings reveal that PGK1 also functions as a protein kinase phosphorylating valosin-containing protein (VCP) at S746, which subsequently reduces Beclin 1 deubiquitination and impairs autophagy. Inhibition of PGK1 initiates autophagy in T315I-mutant chronic myeloid leukemia (CML) cells, thereby enhancing their sensitivity to first-generation Tyrosine Kinase Inhibitor (TKI) imatinib and third-generation TKI ponatinib. Despite the significant clinical implications, few PGK1-targeting inhibitors have been approved for clinical use to date. Through a comprehensive high-throughput screening of ∼20,000 natural compounds, we identified flavonoid as potent inhibitors of the enzymatic activity of PGK1. Subsequent structural optimization of these flavonoid derivatives led to the development of CPU-216, a compound that binds to the GLU344 and PHE292 residues of PGK1, effectively inhibiting its enzymatic and kinase activity. Notably, CPU-216 induces autophagy via VCP and Beclin 1 in CML-T315I cells, enhancing their responsiveness to TKIs. These discoveries propose a novel therapeutic strategy for T315I-mutant CML, underscoring the potential to develop targeted treatments that leverage the kinase functions of PGK1.

A triple combination strategy for nasopharyngeal carcinoma: Aptamer-guided liposomal chemotherapy, engineered NK cells, and Fc-enhanced PD-L1 antibody therapy

Acta Pharmaceutica Sinica B. 2026, 16(3): 1584-1604.

The effective treatment of nasopharyngeal carcinoma (NPC) is challenged by an immunosuppressive tumor microenvironment (TME) and insufficient immune effector cell activation. Herein, we design a synergistic tri-modal therapeutic strategy to overcome these barriers. This platform integrates: (1) a CD109-targeted liposomal doxorubicin (S3-Lip-DOX) for precise chemotherapy and induction of immunogenic cell death (ICD); (2) non-genetically engineered natural killer (NK) cells armed with dual aptamers (targeting CD109 and PD-L1) via bio-orthogonal chemistry for enhanced tumor recognition (S3-P-NK); and (3) an Fc-engineered anti-PD-L1 antibody (Atezolizumab/IgG1) that restores antibody-dependent cellular cytotoxicity (ADCC). Crucially, we uncovered a key mechanistic synergy: S3-Lip-DOX treatment, as a stress-adaptive response, upregulates PD-L1 expression on NPC cells. This finding provides a compelling rationale for the integration, turning a potential immune escape mechanism into a therapeutic vulnerability. The complete regimen, comprising S3-Lip-DOX, S3-P-NK, and Atezolizumab/IgG1, demonstrated potent synergistic antitumor effects in vitro and in vivo. This triple-combination therapy not only achieved significant tumor regression but also robustly reprogrammed the innate tumor microenvironment, evidenced by enhanced dendritic cell (DC) maturation and pro-inflammatory macrophage activation. This work establishes a mechanism-driven, modular therapeutic platform that effectively coordinates targeted chemotherapy with innate immunotherapy, holding significant translational potential for solid tumors.

Single-cell RNA sequencing-guided drug discovery to alleviate radiotherapy-induced esophageal toxicity

Acta Pharmaceutica Sinica B. 2026, 16(3): 1769-1772.

Paeoniflorin alleviates hypobaric hypoxia-triggered lung injury through targeting MEK2 to modulate ERK2-SGK1 signaling

Acta Pharmaceutica Sinica B. 2026, 16(3): 1466-1488.

Hypobaric hypoxia-induced lung injury can exacerbate the incidence of plateau pulmonary edema, but relevant pharmacologic measures are relatively limited. Here, we investigate the possible role of paeoniflorin (Pae) in hypobaric hypoxia-induced lung injury. Through in vivo and in vitro experiments, we observed that Pae significantly ameliorated hypobaric hypoxia-triggered oxidative stress, inflammatory response, mitochondrial dysfunction and ferroptosis. Using limited proteolysis-mass spectrometry (LiP-MS), molecular docking, and molecular dynamics simulations, we identified that Pae directly binds to three amino acid residues (K101, D156, and S198) of the MEK2 protein. Knockdown of MEK2 expression in vivo and in vitro abrogated the protective effect of Pae. It was also observed that Pae promotes the binding of MEK2 and ERK2 and increases the phosphorylation level of ERK2, leading to its activation. This process induced upregulation of SGK1 and the protective effect of Pae against hypobaric hypoxic lung injury was dependent on SGK1. Collectively, these findings provide pharmacological evidence that Pae activates SGK1 by targeting MEK2 and mediating MEK2-ERK2 crosstalk, highlighting Pae's potential as a promising therapeutic agent for hypoxic lung injury-related diseases.

Vitamin A and its analogues modulate MUFAs metabolism to improve ferroptosis and aging by direct targeting of ACSL3

Nanxuan Luo, Yijie Xiao, Yile Zhai, Jie Li, Lijie Lv, Houhua Yin, Fang Lin, Biwen Wan, Ke Zhang, Junchi Hu, Junyan Liu, Yongjun Dang, Yi He, Yahui Zhao, Zhe Zhang, Shenyou Nie, Hai-Xin Yuan

Acta Pharmaceutica Sinica B. 2026, 16(3): 1510-1529.

In our screening campaign for novel ferroptosis inhibitors, we identified that vitamin A (VA) and its metabolite all-trans retinoic acid (ATRA) exhibited potent ferroptosis-suppressing activity. Notably, through a combination of biochemical and pharmacological assays, we demonstrated that the anti-ferroptotic effects of VA and ATRA are independent of both antioxidative mechanisms and the canonical RAR/RXR signaling pathway. This conclusion was corroborated by a series of newly synthesized VA analogues. Furthermore, VA and its structural derivatives significantly alleviated ferroptosis-associated pathological phenotypes in murine models. Intriguingly, we discovered a novel function of VA and its analogues, which directly target acyl-CoA synthetase long-chain family member 3 (ACSL3) and enhance its enzymatic activity. This ACSL3-dependent mechanism increases the MUFA/PUFA ratio in phospholipids, thereby preventing lipid peroxidation. Strikingly, we further demonstrated that VA and its analogue D3 [(2E,4E,6E,8E)-N,3,7-trimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamide] extend the lifespan of C. elegans in a manner dependent on ACSL3, highlighting the physiological relevance of this pathway in aging. Collectively, our findings unveil a previously unrecognized role for VA and its analogues in modulating lipid metabolism, thereby providing a theoretical basis for their potential application in treating ferroptosis-related diseases and possibly enhancing longevity.

Identification of a small-molecule targeting PLAGL2 DNA-binding domain inhibits extracellular matrix formation and enhances lenvatinib sensitivity in hepatocellular carcinoma

Weiwei Hu, Jiaping Ni, Shufang Zheng, Xiaohui Wei, Dongqing Zhai, Jinglin Qi, Xinqi Ye, Mingyin Lu, Hanrui Bian, Jintong Li, Yumeng Shen, Jingwei Jiang, Weijun Zhao, Xueqing Shao, Shihao Xu, Xuewu Liang, Hong Liu, Yong Yang

Acta Pharmaceutica Sinica B. 2026, 16(3): 1489-1509.

The increased stiffness of the extracellular matrix (ECM) is known to promote the progression of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for targeting ECM sensors and remodelers. The objective of this study was to identify the molecular mechanisms underlying the role of Pleomorphic adenoma gene-like 2 (PLAGL2) in HCC ECM remodeling and to formulate compounds that effectively inhibit PLAGL2 transcriptional regulation. Our work revealed that PLAGL2 remodeled the ECM produced by HCC cells via an autocrine mechanism and activated HSCs via a paracrine pathway. Mechanistically, PLAGL2 functioned as a transcriptional regulator of insulin-like growth factor 2 (IGF2) and insulin-like growth factor 1 receptor (IGF1R). IGF2 enhanced ECM remodeling by HCC cells and activated HSCs through the IGF1R-PI3K-Akt signaling pathway. Furthermore, using a computer-aided drug design strategy, a novel compound, DC218, derived from the chemical evolution of cytisine, has been developed for the first time to exhibit specificity as an inhibitor of the PLAGL2 DNA binding domain. DC218 significantly degraded ECM, overcame lenvatinib resistance, and synergistically inhibited HCC. These findings provide mechanistic insight into the role of PLAGL2 in HCC ECM remodeling, as well as suggest a novel strategy for inhibiting ECM and treating HCC.

Membrane-derived biomimetic nanovesicles in anti-tumor immunotherapy: Advances and outlook

Acta Pharmaceutica Sinica B. 2026, 16(3): 1388-1420.

Membrane-derived biomimetic nanovesicles have emerged as a promising platform in cancer immunotherapy due to their intrinsic biocompatibility, functional plasticity, and capability to modulate immune responses. By integrating various immunotherapeutic agents, including immune checkpoint inhibitors, tumor antigens, and immunostimulatory adjuvants, these vesicles can be engineered to mimic natural immune communication and overcome key barriers in the tumor immune microenvironment. This review summarizes recent advances in the design, functionalization, and application of biomimetic nanovesicles for anti-tumor immunity. We particularly highlight strategies that harness these vesicles to enhance innate and adaptive immune responses, reverse immune suppression, and synergize with existing immunotherapy modalities. Furthermore, we discuss the challenges associated with biosafety, large-scale manufacturing, and clinical translation. Continued innovation in vesicle engineering and immunological modulation will be crucial for transforming biomimetic nanovesicles into viable next-generation cancer immunotherapeutics.

Mechanistic insights into ligand selectivity in μ- and δ-opioid receptors beyond the “message-address” conceptual framework

Acta Pharmaceutica Sinica B. 2026, 16(3): 1530-1549.

Ligand selectivity between μ-opioid receptors (μ-OR) and δ-opioid receptors (δ-OR) is key for improving opioid analgesics. While the “message-address” hypothesis has been central to explaining this selectivity, we present evidence for an additional mechanism. Chimeric receptor and mutagenesis studies identify residue 2.63 in the orthosteric pocket as a key determinant of morphine's μ/δ-OR selectivity, while EM-1's selectivity involves a combination of residues at positions 2.63 and 3.29, the N-terminus, and extracellular loop 3 (ECL3). Approaches like voltage-clamp fluorometry, engineered zinc-bridge and microscale thermophoresis show that EM-1's Y¹P²W³F⁴ sequence confers over 1500-fold μ/δ-OR selectivity, driven by steric hindrance and a β-turn structure. β-Endorphin, with a more flexible sequence, binds non-selectively to both receptors. Morphine's rigid isoquinoline scaffold and broader geometry restrict it to binding through the wide ECL2-transmembrane (TM) 5 cleft, explaining its modest μ/δ-OR selectivity. These findings reveal that μ/δ-OR selectivity is driven by both “message-address” interactions and receptor-specific binding pathways, advancing opioid drug design.