Acta Pharmaceutica Sinica B

Liver-pancreas communication in disease and drug development

Acta Pharmaceutica Sinica B. 2026, 16(3): 1250-1271.

The liver and pancreas are metabolically intertwined organs whose bidirectional communication is critical for maintaining systemic homeostasis. Dysregulation of this inter-organ crosstalk is a central driver in the pathology of a growing list of prevalent diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), liver cancer, acute and chronic pancreatitis, and various forms of diabetes. Given the substantial global health burden of these conditions and the lack of effective, Food and Drug Administration (FDA)-approved pharmacological interventions for those diseases, understanding the intricate mechanisms is an urgent and timely endeavor. This review provides a comprehensive synthesis of recent advancements in deciphering the molecular basis of liver-pancreas communication. We explore the multifaceted signaling networks involved, including the roles of liver-derived hepatokines, pancreas-derived hormones, extracellular vesicles, and metabolic exchanges. This axis is further integrated within broader systemic networks involving the gut, neuronal system, adipose tissue, and skeletal muscle. While clinical trials targeting this communication show promise (e.g., FGF21- and bile acid-related drugs), significant challenges remain, particularly the lack of FDA-approved pharmacological treatments for alcohol-associated liver disease (ALD), and acute/chronic pancreatitis. Future research must elucidate specific signaling pathways, identify novel pancreas-derived factors, and develop innovative therapeutic strategies. In particular, small molecule drug discovery based on polypharmacology, for these complex metabolic and organ-specific diseases.

The transcriptional regulatory network involved in periderm-specific tanshinones biosynthesis in Salvia miltiorrhiza root

Acta Pharmaceutica Sinica B. 2026, 16(3): 1568-1583.

Tanshinones (TAs), well-known specialized diterpenoid metabolites in Salvia plants, exhibit distinct tissue-specific production in the root periderm. However, the mechanisms regulating this accumulation pattern remain unknown. Here, we employed a multi-omics analysis strategy to uncover the transcriptional regulatory network responsible for TA biosynthesis in Salvia miltiorrhiza roots. By integrating metabolic profiling, RNA-seq, and ATAC-seq, we profile the temporo-spatial dynamics of metabolic, transcriptional, and chromatin landscapes during early root development. Our results demonstrate that TAs biosynthesis and accumulation in S. miltiorrhiza roots display spatiotemporal patterns, marked by periderm-specific accumulation and initiation exclusively at specific developmental stages, tightly coordinated with dynamic changes in chromatin accessibility and transcriptional regulation. The constructed transcriptional regulatory network driving TA biosynthesis was found to be dominated by 211 key transcription factors (TFs). Experimental validations highlighted SmERF105 as a key positive regulator of TA, activating the transcription of KSL1, CYP76AH3, and the TA transporter ABCG1 to modulate the TA production. Our study uncovers novel, high-confidence regulators and offers an effective strategy for dissecting the genetic basis of plant specialized metabolites, offering value for advancing TA metabolic engineering.

Flavescensines A-L: Novel azaspiro[4.4] heterodimeric alkaloids from Sophora flavescens protect against liver injury by inhibiting DUSP2-mediated mitochondrial apoptosis

Acta Pharmaceutica Sinica B. 2026, 16(3): 1550-1567.

By employing a targeted strategy integrating a building blocks-based molecular network (BBMN), network annotation propagation (NAP), ultraviolet spectroscopy (UV), and mass spectrometry (MS), twelve novel spirocyclic heterodimeric alkaloid flavescensines A-L (1-12) with 5/6/6/6/5 and 6/5/6/6/5 pentacyclic skeletons were isolated from Sophora flavescens. Their structures were unambiguously elucidated through comprehensive spectroscopic data, quantum chemical calculations, and single-crystal X-ray diffraction. Structurally, these compounds represent the first examples of azaspiro[4.4] alkaloids formed through the inert ring A or B of the C₁₅ matrine-type alkaloid and C₉ units. Notably, the NMR signals of C-9′ methylene can serve as diagnostic indicators to determine the absolute configuration of the spiro carbon. A plausible biosynthetic pathway involving an unusual pattern of [3 + 2] cycloaddition was proposed. The hepatoprotective activities of 1-12 were evaluated in vitro, and 10 exhibited the most significant activity. Further in vivo experiments demonstrated that 10 dramatically inhibited the APAP-induced increase in the serum ALT, AST, and LDH levels, reversed the depletion of hepatic GSH, and attenuated hepatic centrilobular necrosis and hemorrhage. Mechanistically, 10 exhibits a potential interaction with DUSP2 and inhibits its expression, thereby suppressing DUSP2-mediated mitochondrial apoptosis via PI3K/Akt/JNK pathway. This represents the first discovery of DUSP2 involving in the hepatoprotection.

bHLH130 mediates gibberellin signaling to regulate tanshinone biosynthesis in Salvia miltiorrhiza

Haizheng Yu, Ruiyang Yao, Sixue Zhang, Yongxing Chen, Caiyan Liang, Yijing Liu, Wenrui Li, Bingcong Xing, Dongfeng Yang, Lei Zhang

Acta Pharmaceutica Sinica B. 2026, 16(3): 1747-1761.

Salvia miltiorrhiza is a prominent traditional Chinese medicinal (TCM) herb with notable therapeutic applications, especially in treatment of cardiovascular and cerebrovascular diseases. A crucial role in promoting tanshinone biosynthesis is attributed to the gibberellic acid (GA) signaling pathway; however, its precise regulatory mechanisms remain incompletely understood. In the current investigation, we identified bHLH130, a GA-responsive bHLH transcription factor (TF), via transcriptomic analysis of GA-treated hairy roots from S. miltiorrhiza. Functional analysis demonstrated that bHLH130 overexpression markedly suppressed tanshinone biosynthesis, whereas its knockout resulted in elevated tanshinone accumulation. Additionally, it was confirmed that bHLH130 directly targets E-box motifs within the promoters of biosynthetic genes, including DXS2, CPS1, KSL1, and CYP76AH1, thereby negatively regulating their transcriptional activities. Moreover, bHLH130 interacts with DELLA4, forming a regulatory complex implicated in the modulation of tanshinone biosynthesis. Co-overexpression assays revealed that DELLA4 attenuated the inhibitory effects of bHLH130 on tanshinone accumulation. Collectively, our data propose that the bHLH130-DELLA4 interaction constitutes a critical regulatory node, balancing GA signaling with secondary metabolite production and offering novel strategies for the metabolic engineering of tanshinones. In conclusion, this research delineates the regulatory role of bHLH130 in tanshinone synthesis, providing valuable insights into the GA-mediated modulation of secondary metabolism.

Dichotomous role of CD47-SIRPα axis: Leveraging opposing functions in phagocytic resistance and transport assistance for enhanced nanocarrier biocompatibility and tumor penetration

Acta Pharmaceutica Sinica B. 2026, 16(3): 1605-1624.

Polyethylene glycol (PEG) carriers can improve drug circulation, but encounter biocompatibility and tumor penetration challenges. The CD47-SIRPα interaction on macrophages can initiate a “don't-eat-me” signal, inhibiting phagocytosis. This study elucidates the dichotomous role of the CD47-SIRPα axis in conferring phagocytosis resistance and transport assistance for enhanced nanocarrier biocompatibility and tumor penetration. Using CD47-functional peptide, we elucidated the capacity of this axis to preserve carrier-cell membrane accessibility, impede macrophage-mediated nanocarrier endocytosis, reduce the secretion of IgG and IgM antibodies, and attenuate complement cascade activation. These mechanisms collectively neutralize the accelerated blood clearance of PEGylated liposomes. Notably, we identified the presence of SIRPα in endothelial vasculature and, for the first time, verified its pivotal role in orchestrating liposomal transit across the endothelial barrier. Moreover, within the tumor region, the CD47-SIRPα axis facilitated carrier hitchhiking on macrophages, enabling deep penetration into the tumor parenchyma and regulating the tumor microenvironment through the differential recognition of M1/M2-type tumor-associated macrophages. This study presents the first evidence of the dichotomous role of the CD47-SIRPα axis in regulating carrier biocompatibility, offering insights into its function to overcome the tumor permeability barrier challenge.

Integrating Chinese medicine and intermittent fasting: A promising approach for treating diabetic vascular calcification

Acta Pharmaceutica Sinica B. 2026, 16(3): 1797-1799.

RDYH58 functionalized exosomes homing muscle fibroblasts for delivery of siRNA targeting FKBP10: A novel therapeutic strategy for idiopathic pulmonary fibrosis

Acta Pharmaceutica Sinica B. 2026, 16(3): 1795-1796.

Targeting immunosuppressive network in glioblastoma: Emerging strategies to overcome immunodeficiency and enhance therapeutic efficacy

Acta Pharmaceutica Sinica B. 2026, 16(3): 1272-1291.

Glioblastoma (GBM), the most aggressive primary brain tumor, remains a formidable therapeutic challenge, with a median survival under 15 months. Despite the current standard of care-comprising maximal safe surgical resection, radiotherapy, and temozolomide chemotherapy-patient outcomes have seen minimal improvement over the past two decades. A key barrier to effective treatment is GBM's robust and multifaceted immunosuppressive network, which critically undermines antitumor immunity. While much of the research has focused on the local immunosuppressive tumor microenvironment, systemic immunosuppression represents an equally important yet often underappreciated obstacle, significantly impairing host immune competence. Effective immunotherapy relies on an intact and functional immune system capable of mounting durable T cell-mediated responses. However, GBM induces profound systemic immune dysfunction, manifested by severe lymphopenia and depletion of effector immune cells, which further limits immune-mediated tumor control. Therefore, a comprehensive understanding of both systemic and local immunosuppressive mechanisms is essential for the rational design of effective immunotherapeutic strategies. In this review, we examine the unique physiological features of the brain, dissect the immunosuppressive landscape of GBM at both local and systemic levels, and highlight recent insights into the underlying mechanisms. We also discuss current immunotherapeutic modalities, and emerging drug delivery strategies aimed at overcoming immunosuppression to improve therapeutic efficacy.

Leveraging vascular normalization via eNOS activation to enhance the efficacy of PD-L1 blockade

Acta Pharmaceutica Sinica B. 2026, 16(3): 1793-1794.

Reversibly unlocking the blood-brain barrier: A study on microtubule dynamics modulation using gold nanoparticle-modified reduced graphene oxide

Acta Pharmaceutica Sinica B. 2026, 16(3): 1676-1695.

The blood-brain barrier (BBB) is a crucial biological interface between the central nervous system and circulation, playing a key role in maintaining the brain's homeostasis and function, but presenting a challenge for drug delivery. Although enhancing the paracellular permeability of the BBB using graphene-based materials (GBMs) is a promising strategy, detailed biological effects and molecular mechanisms remain poorly understood and understudied. In this study, we prepared gold nanoparticle-modified reduced graphene oxide (Au-rGO) sheets as representative GBMs to enhance BBB paracellular permeability transiently. Remarkably, the induced permeability modulation exhibited both significant efficacy and complete reversibility. Biological experiments and molecular dynamics simulations provided full insights into the molecular mechanism of this process, confirming that Au-rGO influences the dynamic equilibrium of MTs by adsorbing soluble tubulins to hinder MT polymerization, and disassembling MTs to promote depolymerization, thus mediating the unlocking of the BBB. Moreover, the subsequent closure of the BBB is mediated by increased MT polymerization, regulated by the activation of the ERK-stathmin pathway. Collectively, this present study comprehensively elucidates the phenomenon of reversible BBB opening induced by Au-rGO and its intricate molecular mechanism, and supports the safety and efficacy of Au-rGO as a paracellular penetration enhancer for enhancing BBB drug delivery efficiency.