# A novel role for decadienyl-L-carnitine in pulmonary vascular remodeling and the underlying interventional mechanism of osthole

## TL;DR

This study shows that decadienyl-L-carnitine (C10:2) promotes lung blood vessel changes in pulmonary hypertension, and osthole can counteract these effects.

## Contribution

The study reveals a new role for C10:2 in pulmonary vascular remodeling and identifies osthole as a potential therapeutic agent.

## Key findings

- C10:2 promotes cell proliferation and extracellular matrix remodeling in pulmonary hypertension.
- Osthole inhibits C10:2-induced pyroptosis and vascular changes by targeting the C10:2/HSP47/NLRP3 axis.
- C10:2 levels correlate with disease progression, suggesting its potential as a diagnostic biomarker.

## Abstract

Pulmonary hypertension (PH) is a severe pulmonary vascular disease lacking early diagnostic biomarker and effective therapeutics. Osthole has capability to alleviate pulmonary vascular remodeling targeting by decadienyl-L-carnitin (C10:2) in PH rats. We sought to explore the novel functional mechanism of C10:2 in cell proliferation, apoptosis, extracellular matrix remodeling, and energy biosynthesis of pulmonary vascular remodeling as well as new inventional mechanism of osthole.

Animal and cell models of PH were established using monocrotaline (MCT) and platelet-derived growth factor-BB (PDGF-BB). C10:2 biosynthesis was manipulated through the administration of exogenous C10:2 and etomoxir. Markers of pyroptosis and pulmonary vascular remodeling, as well as components of the C10:2/HSP47/NLRP3 axis, were evaluated using western blotting, ELISA, and biochemical assays.

Osthole inhibited cell pyroptosis and alleviated pulmonary vascular remodeling by suppressing the expression of NLRP3, GSDMD, Caspase-1, IL-1β, IL-18, and C10:2 in PH rats. Additionally, C10:2 levels were positively correlated with the progression of pulmonary vascular remodeling in a time-dependent manner. C10:2, similar to PDGF-BB, promoted the proliferation of pulmonary arterial smooth muscle cells (PASMCs), accelerated extracellular matrix remodeling, inhibited apoptosis, activated AMPKα-1, and increased ROS accumulation, ultimately leading to mitochondrial dysfunction in PASMCs. Osthole attenuated C10:2-induced pulmonary vascular remodeling by downregulating proliferation markers (PCNA, cyclin A, CDK2), modulating apoptosis markers (Caspase-3, Bax, Bcl-2), inhibiting migration-related proteins (MMP2, MMP9, TGF-β), and reducing AMPKα-1 and ROS overaccumulation as well as HSP47 expression. Collectively, our findings reveal a novel role for C10:2 in accelerating pulmonary vascular remodeling by promoting proliferation, apoptosis resistance, extracellular matrix remodeling, and mitochondrial dysfunction through NLRP3 inflammasome activation. Mechanistically, osthole significantly inhibited pyroptosis and mitigated pulmonary vascular remodeling via the C10:2/HSP47/NLRP3 axis.

Our study identifies a novel function of C10:2 in promoting pyroptosis and accelerating pulmonary vascular remodeling through activation of the HSP47/NLRP3 axis. Furthermore, we demonstrate that osthole effectively inhibits C10:2/HSP47/NLRP3 axis-induced pyroptosis, thereby alleviating pulmonary vascular remodeling. These findings suggest that C10:2 may serve as a potential biomarker for PH diagnosis and provide a foundation for the development of novel anti-PH therapeutic strategies.

The online version contains supplementary material available at 10.1186/s13020-026-01362-8.