Feverfew Compound Parthenolide Eases Skin Fibrosis by Stabilizing Mitochondria-ER Contacts

A compound extracted from feverfew, a medicinal herb used for centuries, may offer a new way to treat localized scleroderma, a chronic disease in which the skin hardens into thickened, fibrotic patches. In a study published in Aging Cell, researchers from West China Hospital of Sichuan University report that parthenolide, a sesquiterpene lactone derived from the plant, alleviates both cellular senescence and skin fibrosis in cell and mouse models of the disease. The team traced the compound’s effects to a surprising destination inside the cell: the delicate contact points where the endoplasmic reticulum reaches over to embrace mitochondria, the organelles that power cellular metabolism.

Localized scleroderma, also called morphea, remains one of the most stubborn fibrotic skin diseases. It causes induration of the dermal and subcutaneous layers, and in severe cases leads to ulcers, disfiguring lesions, joint deformity, restricted movement, and even elevated fracture risk later in life. Current treatment relies mainly on immunosuppressants and glucocorticoids, with emerging options such as tocilizumab and JAK inhibitors, but no available therapy can reverse established skin fibrosis. That therapeutic gap drove the Sichuan team to look deeper into the molecular machinery that keeps fibroblasts, the collagen-producing cells of the dermis, locked in an activated, scar-forming state.

Their starting point was mitochondria. Previous work has established that mitochondrial dysfunction is a core driver of fibroblast activation in scleroderma, and that oxidative stress, a consequence of damaged mitochondria, plays an important role in the disease. Mitochondria are the main source of reactive oxygen species inside cells, and when their calcium handling goes awry, these reactive molecules accumulate and push cells toward senescence, a state of permanent growth arrest. Senescent cells then secrete a cocktail of inflammatory signals known as the senescence-associated secretory phenotype, which promotes fibroblasts and macrophages to adopt a fibrotic phenotype and fuels the scarring process.

Central to mitochondrial calcium control is a structure called the mitochondria-associated endoplasmic reticulum membrane, or MAM. At these contact sites, a channel complex composed of the proteins IP3R1, GRP75, and VDAC1 ferries calcium ions from the endoplasmic reticulum into mitochondria. When this flux becomes excessive, mitochondrial calcium overload damages the organelles, collapses their membrane potential, and elevates production of mitochondrial reactive oxygen species. Using transmission electron microscopy on skin samples from patients treated at West China Hospital between 2024 and 2025, the researchers found that the spatial proximity between the endoplasmic reticulum and mitochondria was significantly reduced in morphea lesions compared with healthy control tissue, providing the first preliminary evidence that MAM homeostasis is disturbed in this disease.

To find a drug that could restore that balance, the team turned to parthenolide, which has documented anti-inflammatory, antioxidative, and antifibrotic effects in liver, lung, kidney, and peritoneal fibrosis models. In human dermal fibroblasts stimulated with TGF-β, the master cytokine of fibrosis, parthenolide treatment reduced the number of β-galactosidase-positive senescent cells, increased proliferation as measured by EdU incorporation, and downregulated the senescence markers p21 and p16 along with the inflammatory cytokines IL-6, IL-1β, and TNF-α. At the highest concentration tested, 5 micromolar over 48 hours, the compound also lowered mRNA and protein levels of α-smooth muscle actin and type I collagen, the hallmarks of myofibroblast activation. Notably, the effects were concentration-dependent, with anti-aging effects appearing at medium and high doses and antifibrotic effects at high doses. When the researchers cleared senescent cells using the dasatinib and quercetin combination, fibroblast activation also eased, supporting the idea that parthenolide relieves fibrosis at least in part by modulating senescence.

The mechanistic hunt then moved to the MAM itself. Confocal microscopy showed that parthenolide diminished the colocalization between mitochondria and the endoplasmic reticulum and increased the inter-organelle distance in activated fibroblasts, while flow cytometry revealed restored mitochondrial membrane potential and reduced reactive oxygen species. RNA sequencing identified 1,111 genes differentially expressed after TGF-β stimulation and 290 after parthenolide treatment, with 161 genes shared between the two sets. Enrichment analyses pointed to wound healing, collagen-containing extracellular matrix, and endoplasmic reticulum lumen pathways. To narrow the field, the researchers performed inverse virtual screening against roughly 2,600 protein structures from the Protein Data Bank, ranking candidates by binding free energy, and intersected the top 100 hits with their differentially expressed genes. Two genes emerged: PI16 and Ero1L.

Ero1L, an oxidoreductase enzyme that lives predominantly at the MAM and responds to hypoxia and oxidative stress, became the prime suspect. Molecular docking predicted that parthenolide binds Ero1L with a binding energy of −7.3 kilocalories per mole, and surface plasmon resonance on a Biacore instrument confirmed a direct physical interaction. Docking simulations highlighted two key residues, ARG-449 and PHE-62, and site-directed mutagenesis showed that converting ARG-449 to alanine abolished the binding affinity, while the PHE-62 mutation had no significant effect, confirming the specificity of the interaction. Parthenolide also reduced Ero1L mRNA and protein expression in TGF-β-treated cells. Single-cell RNA sequencing of a public dataset covering fourteen localized scleroderma patients and fourteen healthy controls, encompassing 32,154 cells clustered into fifteen cell types, showed that Ero1L is expressed at higher levels in activated fibroblasts than in other cell subtypes, and immunohistochemistry revealed elevated Ero1L in patient skin biopsies that correlated positively with both senescence markers and the modified Localized Scleroderma Skin Severity Index.

Causality tests sealed the case. When the researchers overexpressed Ero1L in fibroblasts, the protective effects of parthenolide were reversed: senescence and fibrosis markers climbed back up, mitochondrial reactive oxygen species rose, membrane potential fell, and the compound’s suppression of ER-mitochondrial colocalization was blunted. Conversely, knocking Ero1L down with siRNA mimicked the drug’s benefits, reducing fibrotic and senescent markers, restoring mitochondrial health, increasing the average ER-mitochondria distance on electron micrographs, and weakening the interactions within the IP3R1-GRP75-VDAC1 calcium channel complex. Parthenolide treatment similarly downregulated the three channel proteins and eased mitochondrial calcium overload, suggesting that Ero1L acts upstream of calcium flux at the MAM. The authors propose that Ero1L may also promote fibrosis indirectly through redox regulation, since the enzyme reoxidizes protein disulfide isomerase to maintain the disulfide bonds needed for type I collagen folding and secretion.

Because parthenolide’s poor water solubility and low bioavailability have hindered clinical use, the team engineered a delivery system combining PLGA nanoparticles loaded with the drug and a thermoresponsive F127 poloxamer hydrogel. Electron microscopy showed spherical nanoparticles, and rheological testing confirmed the hydrogel’s injectability and temperature-dependent gel transition at body temperature. High-performance liquid chromatography demonstrated a slower, sustained release without an initial burst phase, and live-dead staining and CCK-8 assays confirmed good biocompatibility. In a bleomycin-induced mouse model of localized scleroderma, weekly injections of the formulation, designated F127@PLGA@PTL at 70 milligrams per kilogram, significantly attenuated dermal thickness, collagen deposition, and myofibroblast counts, reduced Ero1L protein expression, and showed anti-aging effects, while multiplex immunofluorescence indicated the treatment specifically quieted activated fibroblasts without measurable effects on vascular endothelial cells, keratinocytes, or Th2 lymphocytes.

The study is the first to implicate Ero1L in the pathogenesis of localized scleroderma and to demonstrate an anti-aging effect of parthenolide in skin fibrosis, positioning the ER-mitochondrial interface as a therapeutic target for hardening skin diseases. The authors caution that their findings rest on cell culture and mouse models and require validation in human subjects, and they note that parthenolide can behave differently in other contexts, even inducing mitochondrial dysfunction in cancer cells, so its biological effects appear cell-specific and shaped by metabolic state. Still, by connecting a humble herbal compound, a calcium-handling hub, and an aging program into one mechanistic chain, the work opens a concrete path toward therapies that could do what current medicine cannot: soften fibrotic skin by rejuvenating the cells that build it.

Subject of Research: Parthenolide targeting of Ero1L to regulate mitochondria-associated ER membranes in localized scleroderma fibrosis and cellular senescence

Article Title: Targeting Ero1L by Parthenolide Alleviates Cellular Senescence and Fibrosis of Localized Scleroderma by Regulating Mitochondria‐Associated Endoplasmic Reticulum Membranes Stabilization

Article References: Wang, F., Xing, R., Xie, M., Qin, Y., Zhang, Y., Cao, D., He, G., & Lyu, X. (2026). Targeting Ero1L by Parthenolide Alleviates Cellular Senescence and Fibrosis of Localized Scleroderma by Regulating Mitochondria‐Associated Endoplasmic Reticulum Membranes Stabilization. Aging Cell, 25(10), Article e70738. https://doi.org/10.1111/acel.70738

Image Credits: AI Generated

DOI: 10.1111/acel.70738

Keywords: localized scleroderma, parthenolide, Ero1L, mitochondria-associated ER membranes, cellular senescence, fibrosis, calcium flux, dermal fibroblasts, PLGA nanoparticles, F127 hydrogel, oxidative stress, TGF-beta