The primary discoveries are as follows: (i) HSPA5 expression was markedly increased in the TECs of fibrotic kidneys, concurrent with ERS and ferroptosis in UUO-mice; (ii) HSPA5 served as a crucial intermediary in regulating ferroptosis under ERS in renal fibrosis through the utilization of ERS specific inhibitor and ATF4/HSPA5-knockin/-knockdown cellular model. Here, ATF4 is linked to renal fibrosis.