Schaftoside Alleviates Atherosclerosis by Inhibiting the NLRP3 Inflammasome Activation via Chaperone-Mediated Autophagy

Q: What are the key findings of this study?

Schaftoside dose-dependently attenuated atherosclerotic plaque formation in ApoE-/- mice and promoted NLRP3 degradation via binding to LAMP2A (KD=2.58 µM) and HSC70 (KD=67.1 µM).

Q: What is the clinical evidence from this study?

Population: Atherosclerosis. Intervention: Schaftoside vs. Distilled water (vehicle control), MCC950 (20 mg/kg), or AR7 (10 mg/kg). Primary outcome: Atherosclerotic plaque formation, lipid deposition, and NLRP3 inflammasome activation (p=<0.05).

Q: What question did this study set out to answer?

Investigate the therapeutic potential and mechanisms of schaftoside in attenuating atherosclerosis and inhibiting NLRP3 inflammasome activation via chaperone-mediated autophagy.

Miaoyang Lin; Jia He; Yiqin Chen; Jiadi Chen; Yue Li; 朱晓玲; Tong Su; Yuning Jiang; Tiantian Jia; Haiqi Peng; Weixiong Lin; Danping Xu

doi:10.1007/s10753-026-02627-y

October 19, 2026InflammationOpen Access

Schaftoside Alleviates Atherosclerosis by Inhibiting the NLRP3 Inflammasome Activation via Chaperone-Mediated Autophagy

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Key result

Schaftoside attenuates atherosclerotic plaque formation dose-dependently by promoting NLRP3 degradation in preclinical models.

P<0.05

Why the study?

Does schaftoside alleviate high-fat diet-induced atherosclerosis and inhibit NLRP3 inflammasome activation via chaperone-mediated autophagy in ApoE-/- mice and primary peritoneal macrophages?

Key Points

Investigate the therapeutic potential and mechanisms of schaftoside in attenuating atherosclerosis and inhibiting NLRP3 inflammasome activation via chaperone-mediated autophagy.
ApoE ⁻/⁻ mice were fed a high-fat diet for 16 weeks to induce atherosclerosis and treated with oral gavage schaftoside or MCC950 from week 8.
Primary peritoneal macrophages were cultured and challenged with ox-LDL (100 µg/mL) or LPS/ATP to evaluate foam cell formation and inflammasome assembly.
Protein degradation, interaction kinetics, and binding were assessed using cycloheximide chase assays, molecular docking, molecular dynamics simulations, and surface plasmon resonance.
Schaftoside reduced atherosclerotic lesion size, arterial lipid deposition, and serum levels of TC, TG, and LDL-C, while increasing HDL-C in high-fat diet ApoE ⁻/⁻ mice.
Schaftoside decreased protein levels of NLRP3, cleaved Caspase-1, and cleaved IL-1β in vivo and in vitro, without altering their mRNA transcript levels.
Direct binding to CMA regulators LAMP2A (KD = 2.58 µM) and HSC70 (KD = 67.1 µM) promoted lysosomal degradation of NLRP3, which was reversed by NH₄Cl or LAMP2A knockdown.

Structured PICO

Does schaftoside alleviate high-fat diet-induced atherosclerosis and inhibit NLRP3 inflammasome activation via chaperone-mediated autophagy in ApoE-/- mice and primary peritoneal macrophages?

P

Population

Preclinical study in male 6-week-old ApoE-/- mice fed a high-fat diet for 16 weeks and primary peritoneal macrophages stimulated with ox-LDL or LPS/ATP.

I

Intervention

Schaftoside administered daily via intragastric gavage at 20 mg/kg (low dose), 40 mg/kg (medium dose), or 80 mg/kg (high dose) from week 8 to week 16 in vivo; 1, 3, and 6 µM schaftoside incubated for 24 h in vitro.

C

Comparator

Distilled water (daily intragastric administration in normal chow diet and high-fat diet control groups), MCC950 (20 mg/kg daily), or AR7 (10 mg/kg daily) from week 8 to week 16.

O

Outcome

Atherosclerotic lesion area and lipid deposition in the whole aorta and aortic root at 16 weeks, and NLRP3 inflammasome activation/degradation via the LAMP2A-dependent chaperone-mediated autophagy (CMA) pathway.surrogate

Main Result

p-value: p=<0.05

Implication

Preclinical evidence demonstrates that the natural flavone schaftoside attenuates experimental atherosclerosis and hyperlipidemia by enhancing chaperone-mediated autophagic degradation of the NLRP3 inflammasome.

Abstract

Atherosclerosis is a chronic inflammatory disease of the arterial wall and remains the leading cause of cardiovascular events worldwide. Schaftoside is a naturally occurring flavone C-glycoside that improves lipid metabolism and exerts anti-inflammatory effects. However, its atheroprotective effects and anti-inflammatory mechanisms remain unclear. This study explores the therapeutic potential of schaftoside in atherosclerosis and its ability to inhibit NLRP3 inflammasome activation through a LAMP2A-dependent CMA-related lysosomal pathway. We established an high-fat diet (HFD)-induced atherosclerosis model in ApoE ⁻/⁻ mice, along with ox-LDL-induced foam cell formation and LPS/ATP-induced NLRP3 inflammasome activation models in primary peritoneal macrophages (PMs). Atherosclerosis was assessed by lipid deposition and plaque progression in the artery. Foam cell formation was determined by measuring intracellular lipid accumulation and inflammatory responses. The molecular mechanisms by which schaftoside inhibits NLRP3 inflammasome assembly were investigated using Western blotting, immunofluorescence, cycloheximide (CHX) chase assays, molecular docking, molecular dynamics simulations, surface plasmon resonance (SPR), and cell transfection. Schaftoside treatment attenuated atherosclerotic lesions in ApoE ⁻/⁻ mice, as evidenced by reduced plaque formation, diminished lipid deposition, and improved serum lipid profiles. Concurrently, NLRP3 inflammasome activation during atherogenesis was suppressed by schaftoside. This inhibition occurred at the post-translational level of NLRP3 protein and prior to ASC oligomerization. In vitro validation revealed that schaftoside exerted its anti-atherosclerotic effects by promoting NLRP3 protein degradation. CHX chase assays demonstrated that the lysosomal inhibitor NH₄Cl reversed the schaftoside-induced NLRP3 protein degradation. Molecular docking and SPR analyses revealed direct interactions between schaftoside and two key proteins of the CMA pathway, LAMP2A and HSC70. Both in vivo and in vitro experiments supported the involvement of a LAMP2A-dependent CMA-related lysosomal pathway in schaftoside-induced NLRP3 degradation and inhibition of inflammasome assembly. Knockdown of LAMP2A reversed the inhibitory effects of schaftoside on foam cell formation and NLRP3 inflammasome assembly. Schaftoside alleviates HFD-induced atherosclerosis and macrophage-derived foam cell formation while improving lipid metabolism. Moreover, schaftoside suppresses NLRP3 inflammasome activation in atherosclerotic progression through a LAMP2A-dependent CMA-related lysosomal pathway. Schaftoside alleviated atherosclerosis by promoting NLRP3 degradation through a LAMP2A-dependent CMA-related lysosomal pathway, thereby inhibiting inflammasome activation. Created in BioRender

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Cite This Study

Lin et al. (2026) studied Atherosclerosis. Schaftoside vs. Distilled water (vehicle control), MCC950 (20 mg/kg), or AR7 (10 mg/kg) was evaluated on Atherosclerotic plaque formation, lipid deposition, and NLRP3 inflammasome activation (p=<0.05). Schaftoside dose-dependently attenuated atherosclerotic plaque formation in ApoE-/- mice and promoted NLRP3 degradation via binding to LAMP2A (KD=2.58 µM) and HSC70 (KD=67.1 µM).

synapsesocial.com/papers/6ad85566c31ae80836fda6b0 https://doi.org/10.1007/s10753-026-02627-y

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Schaftoside Alleviates Atherosclerosis by Inhibiting the NLRP3 Inflammasome Activation via Chaperone-Mediated Autophagy

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

Schaftoside Alleviates Atherosclerosis by Inhibiting the NLRP3 Inflammasome Activation via Chaperone-Mediated Autophagy

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

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