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Ligen Lin

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Open access Aug 2026

maA dual-target modulator of STK11 and PP2Acα from the flowers of Chrysanthemum indicum mitigates drug-induced liver injury.

INTRODUCTION Hormesis, characterized by low-dose stimulation and high-dose inhibition, is a biphasic regulatory phenomenon, and its underlying mechanisms remain elusive. Drug-induced liver injury (DILI) can progress to liver fibrosis, liver failure, and ultimately death, and natural products hold considerable promise for the treatment of DILI. OBJECTIVES To identify the active constituents and underlying biphasic regulatory mechanism of Chrysanthemum indicum against DILI. METHODS Structural elucidation of the new compounds was achieved through integrated interpretation of HRESIMS, 1D and 2D NMR, and ECD. Signaling pathway was determined by mitochondrial transplantation in vitro and in vivo and RNA sequencing. Target proteins were validated by the drug affinity responsive target stability-mass spectrometry analyses, isothermal titration calorimetry, cellular thermal shift assay, shRNA, and liver-specific knockdown mice. Protein sites were validated by truncation experiments, molecular dynamics simulations, and point mutations. RESULTS A total of 21 guaianolide sesquiterpenoids, including 13 new ones, were isolated and identified from the flowers of C. indicum. Interestingly, the new compound chrysanthemolide I (CI) alleviated acetaminophen-induced liver injury in vitro and in vivo. Mitochondria isolated from CI-treated hepatocytes attenuated DILI. CI attenuated AMP-activated protein kinase (AMPK)-mediated mitochondrial oxidative stress while enhancing AMPK-dependent mitochondrial biogenesis and mitophagy. At low doses, CI binds directly to ALA-205 and ARG-301 of serine/threonine kinase 11 (STK11) with high affinity to activate AMPK; at medium doses, binding of CI to STK11 reaches saturation, leading to peak AMPK activity; at high doses, CI additionally binds to SER-261 of serine/threonine-protein phosphatase 2A catalytic subunit α isoform (PP2Acα) with low affinity to inhibit AMPK activation. Furthermore, liver-specific knockdown of both STK11 and PP2Acα largely diminished the protective effect of CI against DILI. CONCLUSION Novel guaianolide sesquiterpenoid CI was identified as an affinity-dependent dual-target regulator of STK11 and PP2Acα to alleviate DILI.

Fei Zhou, Yu Liu, Haoyu Zhao et al. · Journal of Advanced Research · 0 citations

Aug 2026

GDD, a first-in-class APPL1 activator, restores mitochondrial homeostasis and insulin sensitivity with regulation of LKB1-AMPK axis.

BACKGROUND Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder with increasing morbidity and mortality, and current pharmacotherapies are limited by adverse effects and an inability to reverse the underlying metabolic decline. Tussilago farfara L., a traditional Chinese medicine historically used for diabetes treatment, contains the highly abundant sesquiterpenoid GDD with favorable anti-diabetic properties. METHODS Insulin sensitivity was assessed by 2-NBDG uptake in C2C12 myotubes and in high-fat diet (HFD)-induced mice, while mitochondrial content and function were evaluated via Mito-Tracker staining, ATP content, mitochondrial membrane potential, and mitochondrial ROS. Lip-MS, CETSA, DARTS, SPR, molecular docking, and molecular dynamics simulations were applied to identify and validate the direct target of GDD. RESULTS GDD dose-dependently enhanced insulin-stimulated glucose uptake in C2C12 myotubes, an effect attributed to the clearance of lipotoxic intermediates through mitochondrial biogenesis and functional enhancement, with the LKB1-AMPK cascade participating in this process, as observed in Ampkα1 silencing assay. Critically, GDD bound the PTB domain of APPL1, inhibited its ubiquitination and degradation, and stabilized a conformation favoring APPL1-LKB1 interaction, thereby activating AMPK-related and AMPK-unrelated arms of insulin action. The insulin-sensitizing activity of GDD was abolished in Appl1-silenced cells. In HFD-fed mice, GDD improved insulin sensitivity, reduced fat mass gain, alleviated hyperlipidemia and hepatic steatosis, and restored mitochondrial function in skeletal muscle, with additional protective effects in liver, adipose tissue, pancreas, and kidney. CONCLUSION These findings establish GDD as a first-in-class APPL1 activator that reprograms mitochondrial homeostasis and reinstates insulin signaling, providing proof of concept for pharmacological targeting of APPL1 as a novel anti-diabetic strategy.

Hao Zheng, Ya-Ru Zhao, Xian-Yan Deng et al. · Phytomedicine · 0 citations