PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage

May 18, 2026Autophagy

Pioglitazone reduces joint inflammation and bone damage by activating PPARG, increasing cell cleanup, and lowering inflammatory response

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Abstract

Thiazolidinediones, specifically pioglitazone, demonstrate superior efficacy in alleviating rheumatoid arthritis symptoms compared to other anti-diabetic medications.

Various anti-diabetic medications were assessed for their effects on rheumatoid arthritis models.
Only thiazolidinediones showed significant therapeutic benefits, while other agents had minimal effects.
Thiazolidinediones activate a specific receptor that promotes the removal of damaged cellular components.
This activation helps prevent the activation of a protein complex associated with inflammation.
The reduction of certain inflammatory factors was observed with thiazolidinediones treatment.
Loss of cellular cleaning processes reduced the anti-inflammatory effects of thiazolidinediones in both lab and animal studies.

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Rheumatoidarthritis (RA) is an autoimmune disease accompanied by joint swelling,stiffness, and pain, leading to a sharp decline in quality of life. However,the treatment of RA still faces numerous challenges. Clinical studies indicatethat specific hypoglycemic agents alleviate the symptoms of RA, while the potentialmolecular mechanism remains unknown. Herein, we initially assess the efficacyof various categories of anti-diabetic medications including biguanides, GLP1R(glucagon like peptide 1 receptor) agonists, SLC5A2/SGLT2 (solute carrierfamily 5 member 2) inhibitors, DPP4 (dipeptidyl peptidase 4) inhibitors,sulfonylureas, thiazolidinediones, and insulin analog in RA models ofcollagen-induced arthritis (CIA) and serum-transfer arthritis (STA). Resultsdemonstrate that solely thiazolidinediones (pioglitazone [PIOG]) confersuperior efficacy, whereas the other anti-diabetic agents provide minimal or notherapeutic benefits. Mechanistically, thiazolidinediones (PIOG) activatesPPARG/PPARγ (peroxisome proliferator activated receptor gamma) to promotemitophagic flux, thereby inhibiting aberrant NLRP3 inflammasome activation andreducing pro-inflammatory factors IL1B/IL1-BETA (interleukin 1 beta) and IL18 (interleukin18) release. Notably, loss of autophagy either genetically or pharmacologicallysubstantially diminishes the anti-inflammatory effects of PIOG both in vitroand in vivo. In summary, these results offer new mechanistic insight intodisease crosstalk and support the translational value of thiazolidinedionesPIOG as a candidate for precision therapy in RA or multimorbidity of RA and type2 diabetes mellitus (T2DM).

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PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage

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