Tuoli Tounong decoction promotes lesion resolution in granulomatous lobular mastitis by remodeling a Caspase-8-associated PANoptosis-like cell death network

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Granulomatous lobular mastitis (GLM) is a chronic inflammatory breast disease characterized by granuloma formation, abscesses, fat necrosis, and recurrent tissue injury. This study investigated whether Tuoli Tounong decoction (TTN) promotes lesion resolution in a rat model of GLM by regulating a Caspase-8-associated PANoptosis-like cell death network. Forty-two female Sprague-Dawley rats were used; six served as healthy controls, and the remaining rats underwent GLM model induction and were assigned to the model, supporting method (TF), draining method (TO), TTN, methylprednisolone (MP), or Caspase-8 inhibitor (C8i) groups. Treatments were administered for 21 days. Mammary lesions were evaluated using gross observation, histopathological staining, TUNEL staining, multiplex immunofluorescence, transmission electron microscopy, qPCR, Western blotting, flow cytometry, and ELISA. The model group showed mammary enlargement, inflammatory infiltration, granuloma formation, fat necrosis, collagen deposition, increased pyroptosis-related signaling, and macrophage/myeloid cell remodeling. TTN most effectively reduced lesion size, promoted pus drainage, preserved lobular and ductal architecture, and attenuated fat necrosis and fibrosis. Mechanistically, TTN increased Casp8 mRNA, cleaved Caspase-8, cleaved Caspase-3, and p-MLKL expression while reducing GSDMD membrane-associated accumulation and cleaved GSDMD expression. Casp8 C362S-associated amplification signals were relatively low in the TTN group. Flow cytometry suggested that TTN regulated local myeloid immune remodeling rather than broadly suppressing immune infiltration, whereas serum IL-1β and IL-18 levels showed no significant between-group differences. These findings suggest that TTN alleviates GLM lesions in association with remodeling of a Caspase-8-associated PANoptosis-like cell death network, accompanied by reduced pyroptosis-related injury and increased apoptosis- and p-MLKL-associated signals.

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