Acta Pharmaceutica Sinica B

Reprogramming the spleen-brain axis: Splenic monocyte/macrophage-mediated nanotherapy for ischemic stroke

Xiaodi Shi, Rabeya Jafrin Mow, Chunhua Yang

Acta Pharmaceutica Sinica B. 2026, 16(7): 4746-4747.

Reaction-aware molecular representation learning: Toward generalizable artificial intelligence for enzymatic catalysis

Acta Pharmaceutica Sinica B. 2026, 16(7): 4743-4745.

Harnessing the spleen-brain axis: Magnolol-loaded nanomedicine attenuates ischemic stroke via oxidative stress mitigation and monocyte/macrophage reprogramming

Acta Pharmaceutica Sinica B. 2026, 16(7): 4634-4653.

Cerebral ischemia-reperfusion (I/R) injury is exacerbated by the infiltration of splenic monocytes/macrophages (Mo/Mϕ) via the spleen-brain axis, where splenic-derived Mo/Mϕ migrate to cerebral lesions through C-C chemokine ligand 2/receptor 2 (CCL2/CCR2) chemotaxis, thereby amplifying oxidative stress and the neuroinflammatory cascade. Building on this endogenous pathway, we devised a delivery strategy that utilizes splenic Mo/Mϕ as “living vehicles” for targeted drug delivery. To this end, we developed a spleen-targeted magnolol liposome (Mag-PEG₅K) through optimized PEGylation, ensuring its spleen-specific accumulation and uptake by splenic Mo/Mϕ. After cerebral I/R injury, these nanoparticle-laden cells migrate to the ischemic brain via the CCR2/CCL2 axis to remodel the immunomodulatory microenvironment. This targeted system orchestrates dual therapeutic mechanisms within the lesion: mitochondria-directed reactive oxygen species (ROS) scavenging mitigates oxidative stress and peroxisome proliferator-activated receptor gamma (PPARγ) activation reprograms macrophage polarization, suppressing pro-inflammatory M1 differentiation and curtailing tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) secretion. The attenuated cytokine release suppresses neuronal inflammatory cascades, thereby reducing apoptosis. In vivo, Mag-PEG₅K showed superior efficacy to free magnolol, effectively reducing infarct volume and improving long-term neurological outcomes. Supported by favorable biosafety, this work proposes spleen-targeted nanotherapy as an innovative strategy for reprogramming peripheral immunity via the spleen-brain axis, highlighting the translational potential of Mag-PEG₅K for addressing neuroinflammation and oxidative damage in ischemic stroke.

Targeting FAPα-positive hepatic stellate cells ameliorates the formation of pre-metastatic niche

Acta Pharmaceutica Sinica B. 2026, 16(7): 4426-4441.

The pre-metastatic niche (PMN) serves as a catalyst for tumor metastasis and colonization, involving communication between immune cells and stromal cells. However, less is known about the specific cell-type and their organ-specific functions in PMN formation, with available therapeutic strategies still limited. Here, we identified a significant expression of fibroblast activation protein alpha (FAPα) in hepatic stellate cells (HSCs) associated with the formation of liver PMN, which was dramatically attenuated in HSC-specific conditional Fap-knockout mice. Mechanistically, tumor cell-derived exosomal miR-2467-3p upregulated FAPα expression in HSCs. FAPα⁺ HSCs promoted IL-18 secretion via NF-κB/NLRP3/caspase-1 signaling pathway, which facilitated extracellular matrix (ECM) remodeling and macrophage recruitment. By targeting FAPα⁺ HSCs, the FAPα-activated prodrug Z-GP-DAVLBH disrupted the PMN and suppressed tumor liver metastasis. Collectively, our study emphasizes the crucial role of FAPα⁺ HSCs in the liver PMN and provides a promising therapeutic strategy for tumor metastasis.

Target degradation of CASPASE-1 for alleviation of inflammation in sepsis via optogenetically engineered extracellular vesicles

Acta Pharmaceutica Sinica B. 2026, 16(7): 4692-4705.

Sepsis is a comprehensive ailment of systemic inflammatory response syndrome arising from infection. Activation of CASPASE-1 plays a central role in initiating the inflammatory cascade during sepsis. Herein, we construct optogenetically engineered extracellular vesicles (EVs) that achieve the specific degradation of CASPASE-1 and inhibit sepsis-associated inflammation. Specifically, blue light (460 nm)-induced CRY2/CIBN heterodimerization was applied during the EVs production stage to selectively load GCE-CTM fusion proteins into EVs by EXPLORs technology, yielding EVsGCE⁻CTM loading efficiency compared to conventional methods. Upon systemic delivery, EVsGCE⁻CTM preferentially accumulated in macrophages, where the GCE domain selectively bound activated CASPASE-1. The CTM motif then facilitated its lysosomal degradation by chaperone-mediated autophagy, resulting in potent inhibition of CASPASE-1 activity. In a murine model of sepsis, treatment with EVsGCE⁻CTM effectively attenuated systemic inflammation, reduced multi-organ damage, and significantly improved survival outcomes. This approach enables highly efficient, ubiquitin-independent degradation of intracellular target proteins through macrophage-directed EVs delivery, offering a potential therapeutic approach to address sepsis and other inflammation-related diseases.

Cryptic pockets in proteins: Harnessing conformational dynamics for rational drug design

Feiyue Ma, Shuo Wang, Chunkyu Ko, Meehyein Kim, Peng Zhan

Acta Pharmaceutica Sinica B. 2026, 16(7): 4739-4742.

Hepatic stellate cell enriched Asporin drives liver fibrosis by stabilizing ERH to promote IL-17/MAPK11 signaling

Acta Pharmaceutica Sinica B. 2026, 16(7): 4350-4366.

Liver fibrosis is a pathological process primarily driven by activated hepatic stellate cell (HSC). Single-cell transcriptomics of human fibrotic livers identified ASPN (Asporin) as highly expressed in inflammatory and fibrogenic HSC subsets. Clinically, Asporin was markedly elevated in liver tissue and serum, correlating with fibrosis stage across datasets and cohorts, supporting its potential as a non-invasive biomarker. Functionally, Asporin promoted HSC activation and extracellular matrix (ECM) remodeling, whereas its depletion reduced fibrosis in CCl₄-induced mouse models. Mechanistically, Asporin bound directly to ERH and stabilized it by preventing ubiquitin-mediated degradation. Structural modeling showed Asporin masked ERH's K12 ubiquitination site via hydrogen bonds and hydrophobic interactions. ERH overexpression in HSC activated fibrogenic genes and IL-17 signaling, converging on MAPK11 as a common downstream effector. Notably, ERH knockdown abrogated Asporin-driven profibrotic responses. High throughput screening identified prasugrel, a clinically approved drug, as a potent Asporin suppressor. In CCl₄ and high-fat diet induced fibrosis models, prasugrel alleviated fibrosis, inflammation, lipid accumulation, and portal hypertension by suppressing Asporin and ERH expression. Collectively, these findings define the Asporin/ERH/IL-17/MAPK11 axis as a key mediator of HSC activation and fibrogenesis and highlight prasugrel as a promising anti-fibrotic therapy.

In situ generation of EBNA1 CAR-T cells eradicates antigen specific auto-immune B cells for multiple sclerosis treatment

Acta Pharmaceutica Sinica B. 2026, 16(7): 4676-4691.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Epstein-Barr virus (EBV)-induced B-cell overactivation could lead to inflammatory injury to the CNS, which is thought to underlie the initiation and progression of MS. To specifically eradicate these B cells, we report in situ EBNA1-specific chimeric antigen receptor (CAR)-T cells that were transiently programmed with circular RNA (circRNA)-laden CD7-targeted lipid nanoparticles (CD7-LNP). We demonstrate that systematic injection of CD7-LNP can efficiently introduce CAR circRNA to T lymphocytes and yield in vivo CAR-T cells. These in situ CAR-T cells were able to specifically clear EBNA1-specific B cells and significantly mitigate the progression of MS in a MS mouse model. Thus, in situ generation of EBNA1-specific CAR-T cells hold promise as a therapeutic strategy for MS that avoids the risks of general immunosuppression, and warrant further clinical trials.

Drugging non-canonical kinases in cancer therapeutics: Molecular targets, underlying mechanisms and small-molecule inhibitors

Xuelan Ma, Zhifeng Wen, Zhiwen Wang, Zhiqi Peng, Dongbo Wu, Jun Wang, Bo Liu

Acta Pharmaceutica Sinica B. 2026, 16(7): 4196-4232.

Non-canonical kinases (NCKs) are emerging as druggable targets in oncology, yet a comprehensive map linking their molecular mechanisms and targeting strategies to small-molecule modulators is lacking. Based on the hallmarks of cancer, we explain how NCKs buffer replication stress to preserve genome integrity, reprogram metabolic and stress pathways, coordinate angiogenesis and invasion, and support durable remodeling of the immune-tumor microenvironment. We review preclinical progress from hit identification to lead optimization, highlighting exploitable ATP-site and allosteric pockets, targeted protein degradation, and rational dual-node designs, all supported by structural insights and phenotypic discovery. Early clinical signals from mTOR, ATR, and DNA-PKcs inhibitors, along with late-preclinical programs targeting eEF2K, TBK1, FAM20C, TRPM7, and WNKs, reveal context-dependent NCK vulnerabilities. With further exploration of NCK functions and structures, additional targeted drugs are likely to be developed, potentially transforming non-canonical kinase biology into durable precision oncology.

Scaffold hopping yields novel furo[3,2-d]pyrimidine NNRTIs with optimized antiviral potency, enhanced selectivity, and reduced hERG liability

Acta Pharmaceutica Sinica B. 2026, 16(7): 4459-4477.

Considering the exceptional anti-HIV-1 potency of rilpivirine (RPV) against diverse mutant strains and its remarkable human ether-a-go-go related gene (hERG) potassium channel inhibition (IC₅₀ = 0.50 μmol/L) as well as low selectivity (SI = 3989), a series of novel furo-[3,2-d]pyrimidine derivatives were rationally designed through a scaffold hopping strategy. Encouragingly, compound 10 revealed a striking reduction in hERG channel inhibition (IC₅₀ > 30 μmol/L) and significant increase in selectivity (SI = 161580). Notably, 10 exhibited excellent antiviral activity against various HIV-1 strains (EC₅₀ = 1.9-46.3 nmol/L). In particular, 10 displayed prominent inhibitory potency against Y188L (EC₅₀ = 15.5 nmol/L) and F227L + V106A strain (EC₅₀ = 8.7 nmol/L), which was superior to those of RPV (EC₅₀ ₍Y₁₈₈L₎ = 79.4 nmol/L, EC₅₀ ₍F₂₂₇L ₊ V₁₀₆A₎ = 81.6 nmol/L). Besides, no apparent cytotoxicity (CC₅₀ = 314.8 μmol/L) and negligible suppression of CYP isoenzymes were detected. Overall, these findings illustrated that 10 was a potentially promising NNRTI for HIV-1 therapy.