Atf5, an activating transcription factor, is a cellular prosurvival transcription factor within the basic leucine zipper (bZip) family. It is involved in cellular differentiation, promotes cellular adaptation to stress, and plays a key role in the mammalian mitochondrial unfolded protein response (UPRmt) via mitochondria-nuclear translocation [3,4]. The UPRmt is crucial for maintaining mitochondrial protein homeostasis in response to mitochondrial stress.

In diabetic kidney disease (DKD), ATF5 expression is increased in the kidney tissue of patients and db/db mice, and is tightly correlated with tubular damage. Inhibiting ATF5 in db/db mice using lentiviruses carrying ATF5 shRNA improved serum creatinine, tubulointerstitial fibrosis, and apoptosis, indicating that ATF5 promotes tubulointerstitial injury in DKD by regulating HSP60 and the UPRmt pathway [1]. In the context of cardiomyocyte proliferation, TMEM11 enhances m7G methylation of Atf5 mRNA, increasing ATF5 expression, which promotes the transcription of Inca1 and suppresses cardiomyocyte proliferation. Thus, TMEM11-mediated m7G methylation regulation of Atf5 is involved in cardiomyocyte proliferation [2].

In summary, Atf5 is essential for mitochondrial protein homeostasis through its role in the UPRmt. Studies using gene-knockdown models in DKD and other disease-related models have revealed its promoting role in tubulointerstitial injury in DKD and its inhibitory effect on cardiomyocyte proliferation. These findings suggest that Atf5 could be a potential therapeutic target in related diseases.