Consistent with the findings in Smad3 KO/WT MEFs and SIS3-treated HK-2 cell, disrupted Smad3 largely protected against the loss of renal GPX4 and therefore suppressed expression of 4-HNE and TFR1 and the development of severe renal fibrosis as demonstrated by excessive accumulation of α-SMA, Col-1 and FN in a mouse model of UUO (Figure 5 and Figure S4B). Here, GPX4 is linked to renal fibrosis.