A compound found in several medicinal plants used traditionally across Asia may offer a new way to fight diabetic kidney disease (DKD), according to new research published in the Chinese Journal of Natural Medicines. Scientists at Southern Medical University, in collaboration with Hong Kong Baptist University and other institutions, report that hederagenin — a naturally occurring triterpenoid — can slow kidney aging in diabetes by reversing an epigenetic “off switch” on a powerful anti-aging gene.

DKD is the leading cause of chronic kidney disease worldwide. While newer therapies such as SGLT2 inhibitors can slow its progression, no current treatment fully halts or reverses the decline in kidney function — leaving an urgent need for new therapeutic approaches. A growing body of evidence points to cellular senescence — the accumulation of aged, damaged cells in kidney tissue — as a central driver of the disease, rather than merely a consequence of it.

At the center of the study is Klotho, a gene famously linked to aging and known to protect kidney cells from damage. Analysis of three public gene-expression datasets covering nearly 120 human kidney samples confirmed that Klotho levels are significantly reduced in patients with DKD — and the more advanced the disease, the greater the loss.

But why does Klotho disappear? The researchers zeroed in on DNA methylation, a chemical modification that silences genes without altering the underlying DNA sequence. In kidney cell models of senescence induced by palmitic acid, an elevated fatty acid common in diabetes, methylation of the Klotho gene promoter climbed from about 44.5% to 61.5% — effectively locking the gene down. Levels of DNMT1, the enzyme that maintains these methylation marks, rose in parallel.

Hederagenin reversed this process. In cultured human kidney tubular cells, the compound reduced Klotho promoter methylation, restored Klotho protein levels, curbed DNA damage, and reduced classic hallmarks of senescence including SA-β-gal staining and the cell-cycle inhibitors P16, P21, and P53. The effects mirrored those of 5-azacitidine, an established DNA methylation inhibitor used as a positive control.

A key question in natural product research is whether a compound truly hits its presumed molecular target. Using a suite of orthogonal techniques — molecular docking, 100-nanosecond molecular dynamics simulations, surface plasmon resonance, cellular thermal shift assays (CETSA), and DARTS — the team demonstrated that hederagenin binds directly to DNMT1 with micromolar affinity, comparable to known non-nucleoside DNMT inhibitors. Chromatin immunoprecipitation, EMSA, and DNA pull-down assays further showed that hederagenin physically prevents DNMT1 from docking onto the Klotho promoter.

Genetic experiments confirmed causality: silencing Klotho abolished hederagenin’s anti-senescence protection, while overexpressing DNMT1 accelerated senescence — an effect the compound could largely counteract.

In db/db mice — the standard mouse model of type 2 diabetic kidney disease — 12 weeks of oral hederagenin improved kidney function, reducing blood urea nitrogen, serum creatinine, and 24-hour urinary protein excretion. Notably, hederagenin outperformed the clinical drug dapagliflozin on proteinuria and creatinine endpoints, even though its glucose-lowering effect emerged later. Kidney histology showed reduced fibrosis and cellular senescence, decreased DNA damage (γ-H2AX), and restored Klotho expression.

“We identified hederagenin as a novel epigenetic modulator that counteracts renal senescence by restoring Klotho through inhibition of DNMT1-mediated DNA methylation,” the authors write. The findings support hederagenin’s ethnopharmacological potential for DKD management and position DNMT1 as a druggable epigenetic target in senescence-driven kidney disease.

The authors note that the work remains preclinical: validation in primary human kidney cells, comprehensive dose-response and toxicology studies, and ultimately clinical trials are needed before hederagenin could reach patients.

The work entitled “Hederagenin attenuates renal senescence in diabetic kidney disease by inhibiting DNMT1-mediated Klotho DNA methylation” was published in the Chinese Journal of Natural Medicines (published on August 21, 2026).
DOI：10.1016/S1875-5364(26)61205-8