PPARGC1A and renal fibrosis: Mitochondrial oxidative stress exacerbates the DKD cycle (Ito et al., 2022): (1) High glucose boosts ATP demand, increasing ROS production by mtETC; (2) ROS overproduction damages biomolecules; (3) ROS inhibits mitochondrial growth by downregulating PGC-1α, reducing mtDNA; (4) Diminished mtDNA synthesis impairs electron transport, escalating superoxide generation, further harming mtDNA; (Santos et al., 2011); (5) ROS and impaired mtDNA accumulate over time, resulting in damage to podocytes and renal tubular cells, further worsening renal fibrosis (Huang et al., 2020).