Targeting FOSL1-KCa3.1 inhibits ferroptosis and cartilage destruction by suppressing mitochondrial hyperfusion

Area of Science:

• Biomedical Science
• Molecular Biology
• Immunology

Background:

• Chondrocyte death significantly contributes to cartilage destruction in rheumatoid arthritis (RA).
• The precise mechanisms driving chondrocyte ferroptosis in RA are not fully understood.
• Identifying novel therapeutic targets is crucial for managing RA progression.

Purpose of the Study:

• To investigate the role of the calcium-activated potassium channel KCa3.1 in chondrocyte ferroptosis and cartilage destruction in RA.
• To elucidate the molecular mechanisms linking KCa3.1 to ferroptosis and mitochondrial dysfunction in RA.
• To evaluate the therapeutic potential of targeting the FOSL1-KCa3.1 axis in RA.

Main Methods:

• Genetic ablation and pharmacological inhibition of KCa3.1 in RA models.
• Assessment of lipid peroxidation, reactive oxygen species (ROS), and iron deposition.
• Analysis of mitochondrial morphology and fusion dynamics.
• Investigation of the transcription factor FOSL1 binding to the KCa3.1 promoter.
• Gene silencing and pharmacological inhibition of FOSL1.

Main Results:

• KCa3.1 acts as a critical mediator of chondrocyte ferroptosis and cartilage destruction in RA.
• KCa3.1 inhibition reduced lipid peroxidation, ROS accumulation, and iron deposition, protecting chondrocytes.
• Inhibition of mitochondrial fusion suppressed KCa3.1-mediated ferroptosis.
• FOSL1 directly upregulates KCa3.1 expression, leading to calcium overload, mitochondrial hyperfusion, and ferroptosis.
• FOSL1 targeting reduced KCa3.1 expression, restored mitochondrial homeostasis, and alleviated RA disease progression and cartilage damage.

Conclusions:

• The FOSL1-KCa3.1 signaling axis is a key pathway driving chondrocyte ferroptosis in rheumatoid arthritis.
• Targeting KCa3.1 or FOSL1 presents a promising therapeutic strategy for RA.
• This axis may also be a target for other pathologies involving ferroptosis.