Paeonol Inhibits ACSL4 to Protect Chondrocytes from Ferroptosis and Ameliorates Osteoarthritis Progression

Overview

Journal J Orthop Translat

Publisher Elsevier

Specialty Orthopedics

Date 2024 Dec 11

PMID 39659898

Authors

Siyang Cao

Yihao Wei

Ao Xiong

Yaohang Yue

Jun Yang

Deli Wang

Xiyu Liu

Hui Zeng

Dongquan Shi

Ye Li

Affiliations

Soon will be listed here.

Abstract

Background: Discovering an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein that triggers cell injury via ferroptosis, presents potential to minimize cellular damage. This study investigates paeonol (PAE), a traditional Chinese herbal medicine, as an ACSL4 inhibitor to prevent chondrocyte ferroptosis and protect against osteoarthritis (OA).

Methods: We conducted experiments using mouse chondrocytes treated with PAE to mitigate ferroptosis induced by Interleukin-1 Beta (IL-1β) or ferric ammonium citrate (FAC), examining intracellular ferroptotic indicators, cartilage catabolic markers, and ferroptosis regulatory proteins. A mouse OA model was created via destabilized medial meniscus (DMM), followed by intra-articular PAE injections. After 8 weeks, micro-computed tomography and histological assessments evaluated PAE's protective and anti-ferroptotic effects in the OA model.

Results: results showed PAE significantly reduced IL-1β/FAC-induced damage by targeting ACSL4, including cell apoptosis, inflammatory responses, extracellular matrix degradation, and ferroptotic markers (oxidative stress, lipid peroxidation, and iron buildup). It also restored the expression of ferroptotic suppressors and mitigated mitochondrial damage. Additionally, PAE increased cartilage anabolic marker expression while reducing cartilage catabolic marker expression. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability analysis verified the binding interaction between PAE and ACSL4. Furthermore, the role of PAE in chondrocytes was further verified through ACSL4 knockdown and overexpression. , mice with OA showed increased cartilage degradation and ferroptosis, while intra-articular PAE injection alleviated these pathological changes.

Conclusion: PAE significantly protects chondrocytes from ferroptosis induced by IL-1β/FAC in primary mouse chondrocytes and DMM surgery-induced OA mice through ACSL4 inhibition.

The Translational Potential Of This Article: These findings highlight the potential of targeting ACSL4 in chondrocytes as a treatment strategy for OA, positioning PAE as a promising drug candidate.

References

Wang X, Zhou Y, Min J, Wang F . Zooming in and out of ferroptosis in human disease. Front Med. 2023; 17(2):173-206. DOI: 10.1007/s11684-023-0992-z. View

Xu Y, Yang Z, Dai T, Xue X, Xia D, Feng Z . Characteristics and time points to inhibit ferroptosis in human osteoarthritis. Sci Rep. 2023; 13(1):21592. PMC: 10703773. DOI: 10.1038/s41598-023-49089-y. View

Sechzer J, Rabinowitz V, Denmark F, McGinn M, WEEKS B, Wilkens C . Sex and gender bias in animal research and in clinical studies of cancer, cardiovascular disease, and depression. Ann N Y Acad Sci. 1994; 736:21-48. DOI: 10.1111/j.1749-6632.1994.tb12816.x. View

Saitou T, Kiyomatsu H, Imamura T . Quantitative Morphometry for Osteochondral Tissues Using Second Harmonic Generation Microscopy and Image Texture Information. Sci Rep. 2018; 8(1):2826. PMC: 5809560. DOI: 10.1038/s41598-018-21005-9. View

Blom A, van Lent P, Libregts S, Holthuysen A, van der Kraan P, van Rooijen N . Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum. 2006; 56(1):147-57. DOI: 10.1002/art.22337. View

Latourte A, Kloppenburg M, Richette P . Emerging pharmaceutical therapies for osteoarthritis. Nat Rev Rheumatol. 2020; 16(12):673-688. DOI: 10.1038/s41584-020-00518-6. View

Wu R, Liu Y, Zhang F, Dai S, Xue X, Peng C . Protective mechanism of Paeonol on central nervous system. Phytother Res. 2023; 38(2):470-488. DOI: 10.1002/ptr.8049. View

Malaise O, Tachikart Y, Constantinides M, Mumme M, Ferreira-Lopez R, Noack S . Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development. Aging (Albany NY). 2019; 11(20):9128-9146. PMC: 6834426. DOI: 10.18632/aging.102379. View

Gaschler M, Andia A, Liu H, Csuka J, Hurlocker B, Vaiana C . FINO initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018; 14(5):507-515. PMC: 5899674. DOI: 10.1038/s41589-018-0031-6. View

10.

Ru Q, Li Y, Xie W, Ding Y, Chen L, Xu G . Fighting age-related orthopedic diseases: focusing on ferroptosis. Bone Res. 2023; 11(1):12. PMC: 9975200. DOI: 10.1038/s41413-023-00247-y. View

11.

Zhang H, Hu B, Li Z, Du T, Shan J, Ye Z . PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol. 2022; 24(1):88-98. DOI: 10.1038/s41556-021-00818-3. View

12.

Gao M, Yi J, Zhu J, Minikes A, Monian P, Thompson C . Role of Mitochondria in Ferroptosis. Mol Cell. 2018; 73(2):354-363.e3. PMC: 6338496. DOI: 10.1016/j.molcel.2018.10.042. View

13.

Hunter D, March L, Chew M . Osteoarthritis in 2020 and beyond: a Lancet Commission. Lancet. 2020; 396(10264):1711-1712. DOI: 10.1016/S0140-6736(20)32230-3. View

14.

Pan Z, He Q, Zeng J, Li S, Li M, Chen B . Naringenin protects against iron overload-induced osteoarthritis by suppressing oxidative stress. Phytomedicine. 2022; 105:154330. DOI: 10.1016/j.phymed.2022.154330. View

15.

Zhu R, Wang Y, Ouyang Z, Hao W, Zhou F, Lin Y . Targeting regulated chondrocyte death in osteoarthritis therapy. Biochem Pharmacol. 2023; 215:115707. DOI: 10.1016/j.bcp.2023.115707. View

16.

Schmid R, Schiffner S, Opolka A, Grassel S, Schubert T, Moser M . Enhanced cartilage regeneration in MIA/CD-RAP deficient mice. Cell Death Dis. 2011; 1:e97. PMC: 3032321. DOI: 10.1038/cddis.2010.78. View

17.

Jin L, Alesi G, Kang S . Glutaminolysis as a target for cancer therapy. Oncogene. 2015; 35(28):3619-25. PMC: 5225500. DOI: 10.1038/onc.2015.447. View

18.

Jing X, Lin J, Du T, Jiang Z, Li T, Wang G . Iron Overload Is Associated With Accelerated Progression of Osteoarthritis: The Role of DMT1 Mediated Iron Homeostasis. Front Cell Dev Biol. 2021; 8:594509. PMC: 7813682. DOI: 10.3389/fcell.2020.594509. View

19.

Cao S, Wei Y, Xu H, Weng J, Qi T, Yu F . Crosstalk between ferroptosis and chondrocytes in osteoarthritis: a systematic review of and studies. Front Immunol. 2023; 14:1202436. PMC: 10376718. DOI: 10.3389/fimmu.2023.1202436. View

20.

Jing X, Wang Q, Du T, Zhang W, Liu X, Liu Q . Calcium chelator BAPTA‑AM protects against iron overload‑induced chondrocyte mitochondrial dysfunction and cartilage degeneration. Int J Mol Med. 2021; 48(4). PMC: 8416145. DOI: 10.3892/ijmm.2021.5029. View