Modulation of the SDF-1/CXCR4 Axis by Tithonia Diversifolia, Moringa Oleifera and Curcuma Longa Extracts in Diabetic Fatty Liver

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder often linked to non-alcoholic fatty liver disease (NAFLD). Liver inflammation in T2DM is associated with the activation of stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4. This study aimed to evaluate the effect of herbal combinations of Tithonia diversifolia, Moringa oleifera, and Curcuma longa (TMC) on SDF-1 expression in a T2DM-induced fatty liver mice model and assess their potential as a CXCR4 inhibitors through in silico analysis. The in silico study involved LC-HRMS compound identification, bioactivity prediction, drug-likeness screening, molecular docking, and molecular dynamics simulations to analyze interactions with CXCR4. In the in vivo study, T2DM was induced by a high-fat diet and streptozotocin, followed by 21 days of oral TMC extract administration to evaluate its therapeutic effects. LC-HRMS analysis identified 23 bioactive compounds in TMC extracts, including curcumin, which after screening was used in molecular docking. Curcumin showed the strongest binding to CXCR4 (−6.3 kcal/mol), with residue similarity to IT1t and metformin. The stability of the CXCR4-Curcumin was rigorously confirmed by a 20 ns molecular dynamics simulation. SDF-1 expression was significantly increased in T2DM mice (38.72±6.12%) compared to normal (24.21±4.80%). The combination of TMC extracts, especially TMC3, reduced the expression to 24.59±4.68% which was close to the normal group. This decrease was attributed to the polyphenol and sesquiterpene content, which acted through anti-inflammatory pathways. These results suggest that the TMC herbal combinations have potential as an alternative phytotherapeutic agent acting to inhibit SDF-1 and CXCR4 activation in T2DM-induced fatty liver.