Pioglitazone Mitigates Irinotecan-Induced Intestinal Mucositis

Irinotecan is widely used in metastatic colorectal cancer, but its clinical utility is limited by gastrointestinal toxicity, particularly intestinal mucositis, for which effective therapies are lacking. This study evaluated the protective effects of pioglitazone, a thiazolidinedione PPAR-γ agonist, against irinotecan-induced mucositis in female Swiss mice. Mucositis was induced by irinotecan (75 mg/kg, i.p., for 4 days), followed by pioglitazone treatment (3, 10, and 30 mg/kg orally, or 3 mg/kg intraperitoneally) for 7 days. Pioglitazone at 30 mg/kg (p.o.) significantly reduced diarrhea score and partially restored leukocyte counts and spleen weight, while also improving duodenal weight. Histological analysis revealed preservation of villus structure, crypt integrity, and goblet cell numbers, with reduced inflammatory infiltration and mucosal vacuolization. At the biochemical level, pioglitazone restored superoxide dismutase (SOD) activity, normalized glutathione S-transferase (GST) activity, and markedly decreased myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) activities, although glutathione (GSH) remained depleted and nitrite levels elevated. Collectively, these findings demonstrate that pioglitazone at 30 mg/kg (p.o.) attenuates key clinical, histological, and inflammatory alterations and modulates redox-related parameters associated with irinotecan-induced mucositis. Pioglitazone thus emerges as a promising candidate for repurposing as an adjuvant therapy to improve chemotherapy tolerability in colorectal cancer.