To investigate the mechanism of tanshinone ⅡA (TIIA) in improving diabetic peripheral neuropathy (DPN) by regulating pyroptosis pathway.

(1) Type 2 diabetes mellitus (T2DM)-DPN mouse models was established through high-fat diet feeding combined with intraperitoneal streptozotocin (STZ). The experimental animals were randomly divided into three groups: control group, model group (110 mg/kg STZ-induced), TIIA group (DPN model+20 mg/kg TIIA sodium sulfonate injection), with 10 mice in each group; (2) Pain behavioral assessments were conducted using Von Frey filaments for mechanical allodynia and the hot plate test to quantify thermal hyperalgesia thresholds; (3) Sciatic nerve sections underwent hematoxylin-eosin (HE) staining and Luxol fast blue (LFB) staining for myelin integrity, and transmission electron microscopy (TEM) to evaluate ultrastructural alterations in myelin-axon units; (4) Epidermal nerve fiber density in plantar skin specimens was quantified through immunofluorescence staining using anti-PGP9.5 antibodies; (5) Protein expression levels of nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), cysteinyl aspartate specific proteinase-1 (Caspase-1), gasdermin-D (GSDMD), and interleukin-1β (IL-1β) in sciatic nerves were quantitatively analyzed through Western blot combined with immunofluorescence assay; (6) RSC96 cells were cultured in vitro with hyperglycemic injury model established; (7) Cytotoxic effects of TIIA were assessed using lactate dehydrogenase (LDH) release assay across a concentration gradient (5, 10, 20, 40 μmol/L), with dose-response analysis identifying 20 μmol/L as the optimal therapeutic concentration for subsequent experiments; (8) Schwann cell were divided into three groups: control group (5.5 mmol/L glucose), hyperglycemic injury model group (50 mmol/L glucose), and pharmacological intervention (50 mmol/L glucose + 20 μmol/L TIIA); (9) Intracellular reactive oxygen species (ROS) levels were quantified via flow cytometry using DCFH-DA fluorescent probe; (10) The protein expression levels of NLRP-3, ASC, GSDMD, Caspase-1, and IL-1β in each group were analyze by Western blot.

(1) TIIA ameliorated chronic hyperglycemia-induced myelin sheath structural pathology and neuropathic progression; (2) TIIA treatment significantly ameliorated the loss of intraepidermal nerve fibers density in DPN model mice; (3) TIIA inhibited hyperglycemia-induced ROS overproduction in RSC96 cells; (4) TIIA ameliorates chronic hyperglycemia-induced peripheral neuropathy through inhibiting suppression of NLRP3 inflammasome assembly, Caspase-1-mediated GSDMD cleavage, and subsequent IL-1β secretion, effectively disrupting the pyroptosis-inflammation axis.

TIIA alleviates hyperglycemia-induced peripheral neuropathic damage by scavenging intracellular ROS overaccumulation, thereby blocking NLRP3 inflammasome activation and subsequent Caspase-1/GSDMD-mediated pyroptosis in Schwann cells, ultimately preserving myelin-axon structural integrity.