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Background: Chondrocyte ferroptosis plays a critical role in the pathogenesis of osteoarthritis (OA), regulated by the SLC7A11/GPX4 signaling pathway. Icariin (ICA), a flavonoid glycoside, exhibits strong anti-inflammatory and antioxidant activities. This study investigated whether ICA could modulate the SLC7A11/GPX4 signaling to inhibit chondrocyte ferroptosis and alleviate OA.

Purpose: The objective was to explore the impact of ICA on chondrocyte ferroptosis in OA and its modulation of the SLC7A11/GPX4 signaling pathway.

Methods: The anti-ferroptosis effects of ICA were evaluated in an interleukin-1β (IL-1β)-treated SW1353 cell model, using Ferrostatin-1 (Fer-1) and Erastin (Era) as ferroptosis inhibitor and inducer, respectively, along with GPX4 knockdown via lentivirus-based shRNA. Additionally, the therapeutic efficacy of ICA on OA-related articular cartilage damage was assessed in rats through histopathology and immunohistochemistry (IHC).

Results: IL-1β treatment upregulated the expression of OA-associated matrix metalloproteinases (MMP3 and MMP1), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-5), and increased intracellular ROS, lipid ROS, and MDA levels while downregulating collagen II and SOX9 expression in SW1353 cells. ICA treatment countered the IL-1β-induced upregulation of MMPs and ADAMTS-5, restored collagen II and SOX9 expression, and reduced intracellular ROS, lipid ROS, and MDA levels. Furthermore, IL-1β upregulated P53 but downregulated SLC7A11 and GPX4 expression in SW1353 cells, effects that were mitigated by ICA or Fer-1 treatment. Significantly, ICA also alleviated Era-induced ferroptosis, whereas it had no effect on GPX4-silenced SW1353 cells. In vivo, ICA treatment reduced articular cartilage damage in OA rats by partially restoring collagen II and GPX4 expression, inhibiting cartilage extracellular matrix (ECM) degradation and chondrocyte ferroptosis.

Conclusion: ICA treatment mitigated chondrocyte ferroptosis and articular cartilage damage by enhancing the SLC7A11/GPX4 signaling, suggesting its potential as a therapeutic agent for OA interventions.

Titel:	Icariin inhibits chondrocyte ferroptosis and alleviates osteoarthritis by enhancing the SLC7A11/GPX4 signaling.
Autor/in / Beteiligte Person:	Xiao, J ; Luo, C ; Li, A ; Cai, F ; Wang, Y ; Pan, X ; Xu, L ; Wang, Z ; Xing, Z ; Yu, L ; Chen, Y ; Tian, M
Link:	Zum Volltext
Zeitschrift:	International immunopharmacology, Jg. 133 (2024-05-30), S. 112010
Veröffentlichung:	Amsterdam ; New York : Elsevier Science, c2001-, 2024
Medientyp:	academicJournal
ISSN:	1878-1705 (electronic)
DOI:	10.1016/j.intimp.2024.112010
Schlagwort:	Animals Humans Male Rats Anti-Inflammatory Agents pharmacology Anti-Inflammatory Agents therapeutic use Cartilage, Articular drug effects Cartilage, Articular pathology Cartilage, Articular metabolism Cell Line Interleukin-1beta metabolism Rats, Sprague-Dawley Amino Acid Transport System y+ metabolism Amino Acid Transport System y+ genetics Chondrocytes drug effects Chondrocytes metabolism Ferroptosis drug effects Flavonoids pharmacology Flavonoids therapeutic use Osteoarthritis drug therapy Osteoarthritis metabolism Osteoarthritis pathology Phospholipid Hydroperoxide Glutathione Peroxidase metabolism Phospholipid Hydroperoxide Glutathione Peroxidase genetics Signal Transduction drug effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Int Immunopharmacol] 2024 May 30; Vol. 133, pp. 112010. <i>Date of Electronic Publication: </i>2024 Apr 17. MeSH Terms: Amino Acid Transport System y+* / metabolism ; Amino Acid Transport System y+* / genetics ; Chondrocytes* / drug effects ; Chondrocytes* / metabolism ; Ferroptosis* / drug effects ; Flavonoids* / pharmacology ; Flavonoids* / therapeutic use ; Osteoarthritis* / drug therapy ; Osteoarthritis* / metabolism ; Osteoarthritis* / pathology ; Phospholipid Hydroperoxide Glutathione Peroxidase* / metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase* / genetics ; Signal Transduction* / drug effects ; Animals ; Humans ; Male ; Rats ; Anti-Inflammatory Agents / pharmacology ; Anti-Inflammatory Agents / therapeutic use ; Cartilage, Articular / drug effects ; Cartilage, Articular / pathology ; Cartilage, Articular / metabolism ; Cell Line ; Interleukin-1beta / metabolism ; Rats, Sprague-Dawley Contributed Indexing: Keywords: Chondrocytes; Ferroptosis; Icariin; Osteoarthritis; SLC7A11/GPX4 Substance Nomenclature: 0 (Amino Acid Transport System y+) ; 0 (Anti-Inflammatory Agents) ; 0 (Flavonoids) ; EC 1.11.1.9 (glutathione peroxidase 4, rat) ; VNM47R2QSQ (icariin) ; 0 (Interleukin-1beta) ; EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase) ; 0 (SLC7A11 protein, human) Entry Date(s): Date Created: 20240418 Date Completed: 20240511 Latest Revision: 20240618 Update Code: 20240618

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Icariin inhibits chondrocyte ferroptosis and alleviates osteoarthritis by enhancing the SLC7A11/GPX4 signaling.