“Multiomics” Analyses Combined with Systems Pharmacology Reveal the Renoprotection of Mangiferin Monosodium Salt in Rats with Diabetic Nephropathy: Focus on Improvements in Renal Ferroptosis, Renal Inflammation, and Podocyte Insulin Resistance

Abstract

We explored the protection of mangiferin monosodium salt (MGM) on kidney injury in rats with streptozotocin (STZ)-induced diabetic nephropathy (DN) by “multiomics” analysis combined with systems pharmacology, with a specific focus on ferroptosis, inflammation, and podocyte insulin resistance (IR) signaling events in kidneys. MGM treatment afforded renoprotective effects on rats with STZ-induced DN by alleviating systemic IR-induced renal inflammation and podocyte IR. These mechanisms were correlated mainly with the MGM treatment-induced inhibition of the mitogen-activated protein kinase/nuclear factor-kappa B axis and activation of the phosphorylated insulin receptor substrate 1(Tyr608)/phosphorylated phosphatidylinositol 3-kinase/phosphorylated protein kinase B axis in the kidneys of DN rats. MGM had an ameliorative function in renal ferroptosis in rats with STZ-induced DN by upregulating mevalonate-mediated antioxidant capacities (glutathione peroxidase 4 and ferroptosis suppressor protein 1/coenzyme Q10 axis) and weakening acyl-CoA synthetase long-chain family member 4-mediated proferroptotic generation of lipid drivers in kidneys. MGM may be a promising alternative strategy for the treatment of DN.

Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy

“…Another study revealed a Gpx4/ferroptosis suppressor protein 1/CoQ10 axis in podocytes, which meliorate renal ferroptosis. Then, utilizing systems pharmacology and ‘multi-omics’ analysis, researchers discovered the role of mangiferin monosodium salt (MGM), which inhibits lipid driver ACSL-4-mediated pro-ferroptosis synthesis in the kidney [ 60 ].…”

“…In addition, some extracts from fruits and plants are useful. Mangiferin monosodium salt (MGM), a special component of mango, has also demonstrated a systemic protective role in DN by regulating lipid metabolism derange­ments and arachidonic acid (AA) metabolism [ 60 ]. A few plant extracts, like as Vitexin, are significant bioactive flavonoid monomers that demonstrate their anti-ferroptosis functions via stimulating GPX4 signaling [ 66 ].…”

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

“…99 Recent therapeutic interventions, such as mangiferin monosodium salt, Ginkgolide B, and germacrone, target ferroptosis suppression and are effective in managing diabetic nephropathy through minimizing oxidative stress. 98,100,101 There is currently a paucity of evidence linking ferroptosis directly to podocytes in LN patients; however, recent magnetic resonance analyses referencing three single-nucleotide polymorphisms (rs855791, rs1800562, and rs1799945, which were identified in an expansive genome-wide association study) have associated serum iron levels with susceptibility to SLE. 97 Podocyte ferroptosis might have significant implications for LN patients, whether directly or indirectly.…”

“…Compounds that inhibit ferroptosis, such as ferrostatin‐1, exhibit therapeutic potential by mitigating the expression of GPX4 in podocytes, resulting in a marked reduction of proteinuria and a decrease in podocyte mortality in focal segmental glomerulosclerosis patients 99 . Recent therapeutic interventions, such as mangiferin monosodium salt, Ginkgolide B, and germacrone, target ferroptosis suppression and are effective in managing diabetic nephropathy through minimizing oxidative stress 98,100,101 …”

Ferroptosis: an important player in the inflammatory response in diabetic nephropathy

“…These effects are mainly attributable to the inhibition of the MAPK/NF-κB pathway and activation of the phosphorylated insulin receptor substrate 1 (Tyr608)/phosphorylated PI3K/phosphorylated Akt pathway in the DN rat kidney. MGM ameliorated renal ferroptosis in STZ-induced DN rats by upregulating mevalonate (MVA)-mediated antioxidant capacity (Gpx4 and FSP1/CoQ10 axis) and attenuating ACSL4-mediated renal lipid driver production ( 212 ).…”