Acta Pharmaceutica Sinica B

Gambogenic acid ameliorates inflammation by inhibiting HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis

Huanhuan Pang, Honglin Chen, Peng Chen, Xu Wei, Hongda Liu, Xueling He, Yang Yang, Junzhe Zhang, Dianfei Li, Linlin Lou, Wen Xie, Chong Qiu, Fei Xia, Qiuyan Guo, Shengnan Shen, Qiaoli Shi, Weiguang Li, Guang Han, Xijun Wang, Jigang Wang, Chengchao Xu

Acta Pharmaceutica Sinica B. 2026, 16(1): 337-351.

Sepsis is a life-threatening disease caused by the dysregulated host immune response to infection, which eventually leads to multi-organ failure. Current therapeutic strategies rely heavily on antibiotics. However, conventional antimicrobial therapy often leads to antibiotic abuse and resistance. Therefore, it is of utmost importance to develop new agents for treating sepsis. Here, we demonstrated that gambogenic acid (GNA) not only restricted the release of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated macrophages but also attenuated the inflammatory response and organ damage in septic mice. By using the activity-based protein profiling (ABPP) strategy, we identified 30 potential target proteins of GNA. Among these potential targets, we found that GNA directly bound to the Cys684 residue of hexokinase 1 (HK1) and affected its enzyme activity and cellular localization. These findings were confirmed by the cellular thermal shift assay (CETSA), bio-layer interferometry (BLI), and single-site mutation experiments. Functionally, siHK1 alleviated the Warburg effect, suppressed the activation of NLRP3 inflammasome, and eventually suppressed the release of inflammatory cytokines. Taken together, our findings demonstrated that GNA could attenuate inflammation by alleviating HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis and could serve as a novel therapeutic agent for sepsis and inflammatory disorders.

Neg-entropy is the true drug target for chronic diseases

Acta Pharmaceutica Sinica B. 2026, 16(1): 231-238.

Molecular mechanisms of chronic diseases are complicated, and it impedes drug target identification and subsequent drug discovery. We consider entropy increase in human body the root causes of chronic diseases. Accordingly, the inherent neg-entropic mechanisms, for instance the homeostatic mechanisms for metabolism, immunity, self-healing, etc., are true drug targets. Only very few molecules (such as proteins) are decisive for neg-entropy related functions, thus they are termed “head goose molecules” (HGMs) here. Identification of HGMs is key to activating neg-entropic mechanism(s), and drug intervention of the HGMs’ functions might reprogram the disease process through a neg-entropy mediated drug cloud (dCloud) effect, resulting in a treatment of both symptoms and root causes of the diseases. Thus, we recommend, for the first time, the “HGMs-neg-entropy-dCloud” axis as an important strategy for discovering new drugs. Clinically proven effective drugs that target HGMs are given as examples to illustrate the concept. Different from most of the single-target drugs that interrupt disease signal pathway(s), neg-entropy drugs treat chronic diseases through converting disorderliness to orderliness in the body of patients. We hope it to be helpful in future drug discovery for chronic diseases.

An innovative and stable mRNA-LNP microneedle vaccine elicits humoral and multifunctional cellular immune responses

Xiaoxuan Hong, Xianfu Li, Xiaolu Han, Jinghu Lou, Yue Li, Jintao Lin, Yi Cheng, Haonan Xing, Hui Zhang, Xiwei Wang, Shuang Zhang, Nan Liu, Zengming Wang, Chunying Cui, Aiping Zheng

Acta Pharmaceutica Sinica B. 2026, 16(1): 503-521.

During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro. We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.

Structural biology of HIV-1 reverse transcriptase allosteric inhibitors for drug design

Acta Pharmaceutica Sinica B. 2026, 16(1): 93-121.

HIV-1 reverse transcriptase (RT) is responsible for reverse transcription of viral single-stranded RNA to double-stranded DNA, which plays an important role in the replication cycle of HIV-1 and has been identified as a key target for anti-HIV-1 drug discovery. Among HIV-1 RT inhibitors, allosteric inhibitors acting on non-catalytic sites have the advantages of high efficiency and low cytotoxicity, which are the focus of the research on anti-HIV-1 inhibitors. Great progress has been achieved in the structural biology of HIV-1 RT, which significantly facilitated the development of RT allosteric inhibitors. Herein, we provided a detailed review of the co-crystal structures of small molecule allosteric inhibitors in complex with RT reported in the last decade. Moreover, the strategies to discover novel and efficient inhibitors based on co-crystal structures have also been discussed, expecting to provide a reference for the development of the next-generation anti-HIV-1 drugs.

USP10-mediated deubiquitination and activation of KRAS mutants promotes colorectal cancer via a novel USP10/KRAS positive feedback circuit

Acta Pharmaceutica Sinica B. 2026, 16(1): 322-336.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is associated with the poor prognosis of colorectal cancer (CRC) patients, but the therapeutic strategies targeting KRAS are limited, and novel intervention strategies are urgently needed. The dysfunction of deubiquitinases (DUBs) is widely involved in the progression of malignancy, and DUBs are considered ideal anti-tumor targets due to their well-defined structures and catalytic sites. In our study, through DUB inhibitors screening and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we identified that ubiquitin-specific protease 10 (USP10) functions as a potent DUB regulating KRAS mutants' activity. Mechanistically, USP10 directly binds to and promotes KRAS variants' activity across different mutants by removing the latter’s non-proteolytic ubiquitination chains mainly containing K6, K11, K27 and K29-linkage; while the activated KRAS mutants reciprocally upregulate USP10 levels by phosphorylating the latter at Thr42/Ser337, therefore forming a positive feedback circuit and synergistically promoting KRAS-mutant CRC growth. Moreover, we found that USP10 is elevated in KRAS-mutant CRC tissues and depletion of USP10 preferentially impeded KRAS-mutant CRC growth in vitro/in vivo. Our findings not only uncover the critical roles of the USP10/KRAS positive feedback circuit in promoting KRAS-mutant CRC growth, but also offer novel therapeutic strategies for CRC patients harboring KRAS variants across different mutants by targeting USP10.

Oral administration of probiotic colony-like micro-nano system for immunoregulation of rheumatoid arthritis

Acta Pharmaceutica Sinica B. 2026, 16(1): 444-457.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that requires long-term pharmacological management. Melittin, a peptide derived from bee venom, has shown promising therapeutic efficacy for RA by modulating immune balance. Given the critical role of the gut in immune regulation, oral administration of melittin could have significant clinical implications. However, this approach faces substantial challenges, including degradation by gastric fluids and off-target adverse effects, which compromise its efficacy and safety. To address these limitations, we developed an innovative orally administered, gut-targeted micro-nano system (SPM/AlgL) inspired by bacterial colonies. Herein, gas-shearing microfluidics is leveraged to monodisperse sialic acid-decorated peptide nanomedicines within calcium alginate microgels. These microspheres are then coated with probiotic biofilms, leveraging their acid resistance and intestinal adhesion properties. The biofilm coating effectively protects melittin from gastric degradation and enhances its accumulation in the mesenteric lymph nodes, thereby improving its targeting ability to inflammatory sites and reducing adverse effects. By modulating the Th1/Th2 and Th17/Treg ratios in the mesenteric lymph nodes and spleen tissues, this system successfully alleviates immune responses and efficiently mitigates the progression of arthritis. Overall, this oral therapeutic strategy demonstrates significant potential for advancing the immunotherapy of RA and other systemic autoimmune diseases.

Attenuated Salmonella secreting interleukin-21 activates T-cells and induces anti-tumor effects

Acta Pharmaceutica Sinica B. 2026, 16(1): 239-251.

The tumor microenvironment is characterized by an immunosuppressive state. Although PD-1/PD-L1 blockade therapy activates the immune system against tumors, it has limited long-term efficacy, prompting the development of combination therapies with targeted treatments to improve cancer treatment outcomes. Recent advancements have revitalized interest in using attenuated Salmonella strains as cancer therapeutics that target tumors, induce immune responses, and promote tumor cell death, although complete tumor suppression remains challenging. We aimed to induce antitumor effects by activating the suppressed immune system within the tumor microenvironment using Salmonella-mediated secretion of interleukin-21 (IL-21). We used the tumor-targeting ability of Salmonella and its flagellar type-3 secretion system (FT3SS) to induce the secretion of IL-21 into the tumor microenvironment via the flagellar system and evaluated the local immune response. We also evaluated the efficacy of combining Salmonella-mediated IL-21 delivery and anti-PD-L1 therapy in a mouse model. IL-21 secretion promoted the recruitment of CD4⁺ and CD8⁺ T cells and enhanced the expression of cytotoxicity-related molecules. Tumor-bearing mice treated with the combination therapy with anti-PD-L1 antibodies showed improved survival rates and enhanced tumor growth inhibition. This study demonstrates the tumor-targeting capability and in vivo safety of Salmonella, highlighting its potential as a powerful cancer therapy platform.

Palmitoylation of Tfr1 enhances platelet ferroptosis and liver injury in heat stroke

Acta Pharmaceutica Sinica B. 2026, 16(1): 270-286.

Heat stroke (HS) is a severe medical emergency characterized by coagulation and high mortality due to organ injury. This study identifies a novel mechanism in which platelet ferroptosis, driven by transferrin receptor 1 (Tfr1) palmitoylation, significantly contributes to liver injury in HS. Our findings reveal a strong inverse correlation between platelet count and organ damage, especially liver injury, as well as mortality rates. Using murine models, we demonstrate that inhibiting Tfr1-mediated ferroptosis in platelets mitigates thrombocytopenia and decreases Interleukin-1β (IL-1β) secretion, thereby improving liver function and survival outcomes. This research highlights Tfr1 palmitoylation as a critical factor in iron transport within platelets, with the palmitoylation inhibitor 2-bromopalmitate (2BP) effectively reducing total iron, Fe²⁺, lipid ROS, 4-hydroxynonenal (4-HNE), and cell cytotoxicity under heat stress. These results suggest that targeting Tfr1 palmitoylation-dependent ferroptosis in platelets offers a novel therapeutic strategy for treating HS-induced thrombocytopenia and liver injury.

Engineered cyclic peptide targeting ITGA5 disrupts tumor-stroma interaction to overcome desmoplasia and resistance in pancreatic ductal adenocarcinoma

Deby Fajar Mardhian, Kunal P. Pednekar, Ahmed G. Hemdan, Praneeth Reddy Kuninty, Saadia A. Karim, Sabine de Winter, Josbert M. Metselaar, Jennifer P. Morton, Jai Prakash

Acta Pharmaceutica Sinica B. 2026, 16(1): 305-321.

The tumor-stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma (PDAC), leading to treatment failure. Cancer-associated fibroblasts (CAFs), a key cell type in the stroma, produce abundant extracellular matrix (ECM) and exhibit crosstalk with cancer cells inducing chemoresistance. In this study, we designed a cyclic peptide (cyAV3.3) targeting integrin α5 (ITGA5) to disrupt CAF-induced desmoplasia and crosstalk with cancer cells. In vitro, cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production. In 3D co-cultured human spheroid models, the peptide decreased markers of resistance (ABCG1, BCL2, CXCR4), stemness (WNT1, CD44) and ECM remodeling (COL1A1, MMP2/9, LOX) and enhanced gemcitabine efficacy. In vivo, radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model. Intriguingly, combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered LSL-KrasG¹²D/⁺ LSL-Trp53R¹⁷²H/⁺ Pdx1-Cre (KPC) PDAC models. These effects were attributed to reduced desmoplasia, vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis. This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor-stroma interaction and thereby reduce desmoplasia and resistance, ultimately enhancing chemotherapy efficacy in PDAC.

Construction of a localized immune niche via supramolecular hydrogel vaccine to elicit durable and enhanced immunity against infectious diseases

Qi Shang, Chenwei Jiang, Xiaolong Wang, Mingmei Guo, Jing Liu, Zhedong Jin, Yunsheng Yuan, Feihu Wang

Acta Pharmaceutica Sinica B. 2026, 16(1): 470-483.

Vaccines represent one of the most potent strategies for protecting humans from the threat of infectious diseases. Conventional vaccines elicit acquired immunity by mimicking pathogen characteristics; however, their protective efficacy is limited by inadequate spatiotemporal control of antigen delivery, resulting in suboptimal antigen exposure in lymphoid tissues and transient adaptive immune activation. Here, we developed a self-assembling peptide-based supramolecular hydrogel vaccine to establish a localized immune niche, demonstrating its remarkable efficacy in inducing durable and potent immunity against infectious diseases. We found that this in situ-formed supramolecular hydrogel vaccine serves as a reservoir for antigens and adjuvants while recruiting antigen-presenting dendritic cells (DCs) to accumulate within the scaffold. With the aid of adjuvant, the DCs exhibit enhanced antigen processing and presentation, creating an immunologically active niche that triggers robust B cell and T cell responses. Following a single vaccination, mice immunized with the hydrogel vaccine developed robust humoral immunity and sustained antibody production for 112 days, achieving potent neutralization activity. This study offers a novel approach to spatiotemporal control of vaccine responses that enables durable and enhanced immunity against infectious diseases.