Author: De Winter, Vicky ; Sisto, Angela ; Asselbergh, Bob ; Gatto, Pamela ; Provenzani, Alessandro ; van Wermeskerken, Tamira ; Timmerman, Vincent ; Adami, Valentina ; Pancher, Michael ; Assunção Carreira, Ágata Sofia

HSPB1 [heat shock protein family B (small) member 1] and HSPB8 are essential molecular chaperones for neuronal proteostasis, as they prevent protein aggregation. Mutant HSPB1 and HSPB8 primarily harm peripheral neurons, resulting in axonal Charcot-Marie-Tooth neuropathies (CMT2). Macroautophagy/autophagy is a shared mechanism by which HSPB1 and HSPB8 mutations cause neuronal dysfunction. Autophagosome formation is reduced in mutant HSPB1-induced pluripotent stem-cell-derived motor neurons from CMT type 2F patients. Likewise, the HSPB8^K141N knockin mouse model, mimicking CMT type 2 L, exhibits axonal degeneration and muscle atrophy, with SQSTM1/p62-positive deposits. We show here that mouse embryonic fibroblasts isolated from a HSPB8^K141N/green fluorescent protein (GFP)-LC3 model have diminished autophagosome production under conditions of MTOR inhibition. To correct the autophagic deficits in the HSPB1 and HSPB8 models, we screened by high-throughput autophagosome quantification the repurposing Spectrum Collection library for molecules that could boost the autophagic activity above the canonical MTOR inhibition. Hit compounds were validated on motor neurons obtained by differentiation of HSPB1^P182L and HSPB8^K141N patient-derived induced pluripotent stem cells, focusing on autophagy induction as well as neurite network density, axonal degeneration, and mitochondrial morphology. We identified molecules that specifically stimulate autophagosome formation in the HSPB8^K141N cells, without affecting autophagy flux. Two top lead compounds induced autophagy and reduced axonal degeneration, thus promoting neuronal network maturation in the CMT2 patient-derived motor neurons. Based on these findings, the phenotypical screen revealed that piplartine rescued autophagy deficiencies in both the HSPB1 and HSPB8 models, demonstrating autophagy induction as an effective therapeutic strategy for CMT neuropathies and other chaperonopathies.

01 May 2025·Phytomedicine

Piperlongumine alleviates viral myocarditis by inhibiting pyroptosis through NF-κB pathway

Article

Author: Li, Hui ; Guo, Hengzhong ; Qiu, Yuting ; Wang, Min ; Zou, Yu ; Zhang, Zhengyang ; Hua, Zhengdong ; Lu, Lili

BACKGROUNDViral myocarditis (VMC) is a cardiac condition characterized by inflammation of the myocardium due to viral infection. It is a significant cause of sudden cardiac death in young adults, and effective treatments remain limited. Inflammatory caspase-mediated pyroptosis serves as a host defense mechanism against pathogens and is crucial in the pathogenesis of VMC. Piperlongumine (PL), an amide alkaloid derived from Piper longum l., exhibits notable anti-inflammatory properties. However, there has been no reported research on the use of PL for the treatment of VMC.PURPOSETo explore the role of PL in inhibiting VMC by regulating cardiomyocyte pyroptosis and the potential molecular mechanism.METHODSTo evaluate the effect of PL on VMC, we established the VMC mouse model through intraperitoneal injection of coxsackie virus B3 (CVB3) for in vivo experiments. Subsequently, we assessed body weight, cardiac histopathological changes, cardiac function, and cardiomyocyte pyroptosis in VMC mice following PL treatment using hematoxylin and eosin (HE) staining, echocardiography, real-time quantitative PCR (RT-qPCR), and western blot analysis. The impact of PL on mouse cardiac muscle cell line (HL-1) pyroptosis was evaluated through the cell counting kit-8 assay kit (CCK8), RT-qPCR, immunofluorescence, and western blot. Additionally, network pharmacology was employed to preliminarily analyze the cellular pathways by which PL reduces VMC via the inhibition of pyroptosis, and the results of this analysis were validated through western blot.RESULTSIn vivo experimental results demonstrated that following PL treatment, symptoms in VMC mice were significantly alleviated, cardiac function was restored, inflammation in cardiac tissue was reduced, and both myocardial cell pyroptosis and levels of inflammatory factors were notably decreased. Similar findings were observed in vitro. Network pharmacology analysis indicated that the NF-κB pathway may serve as a critical target for PL treatment of VMC. Furthermore, in vitro experiments revealed that the specific NF-κB pathway inhibitor MG132 can significantly inhibit CVB3-induced pyroptosis. Additionally, PL could reduce the phosphorylation levels of key molecules in the NF-κB signal pathway in a dose dependent manner.CONCLUSIONIn summary, this study presents evidence that PL ameliorates cardiomyocyte injury and enhances cardiac function in VMC mice, by reducing pyroptosis through the inhibition of the NF-κB pathway. These findings offer new insights for the potential of PL in VMC treatment.

24 Mar 2025·JCI Insight

Piperlongumine overcomes osimertinib resistance via governing ubiquitination-modulated Sp1 turnover

Article

Author: Wang, Qiang ; Liao, Jinzhuang ; Yu, Xinfang ; Wang, Ruirui ; Li, Wei

Non-small cell lung cancer (NSCLC) is a common cause of cancer-related deaths worldwide, and its incidence has been increasing in recent years. While targeted therapies like osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor, have brought about notable improvements in patient outcomes for advanced NSCLC, the challenge of acquired drug resistance persists. Here, we found that cellular mesenchymal-epithelial transition factor (c-Met) was highly expressed in osimertinib-resistant cells, and depletion of c-Met markedly inhibited the growth of osimertinib-resistant cells ex vivo and in vivo, suggesting that c-Met is a potential target to address osimertinib resistance. Through a screening process using a natural product compound library, we identified piperlongumine as a potent inhibitor to overcome osimertinib resistance. Furthermore, the combined treatment of piperlongumine and osimertinib exhibited robust antitumor effects in resistant cells, partially restoring their sensitivity to osimertinib. Additionally, we discovered that piperlongumine could enhance the interaction between E3 ligase RNF4 and Sp1, inhibit the phosphorylation of Sp1 at Thr739, facilitate the ubiquitination and degradation of Sp1, lead to c-Met destabilization, and trigger intrinsic apoptosis in resistant cells. In summary, our study sheds light on the potential of piperlongumine in overcoming osimertinib resistance, offering new strategies and perspectives for the clinical management of drug-resistant NSCLC.

100 Deals associated with Piperlongumine

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Indication	Highest Phase	Country/Location	Organization	Date
Glioma	Preclinical	United States	TargTex SA	19 Sep 2023
Breast Cancer	Preclinical	United States	Harvard Medical School	13 Jul 2011

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