Pharmacological modulation of ATF6: exploiting a stress-integrative node to overcome drug resistance.

Activating transcription factor 6 (ATF6), a major arm of the unfolded protein response (UPR), functions as an integrative regulator of cellular adaptation. Beyond proteostasis, ATF6 coordinates redox balance, autophagy, apoptosis, and lipid metabolism. In cancer, aberrant ATF6 signaling promotes proliferation, chemoresistance, ferroptosis evasion, and genome stability through proteolytic activation inflammatory coupling, and post-translation regulation. Crucially, human ATF6 loss‑of‑function mutations cause a blindness-deafness syndrome poorly recapitulated in mice, highlighting potential safety concerns for systemic inhibition. In this review, we summarize ATF6 activation mechanisms, its crosstalk with autophagy and apoptosis, and pharmacological strategies, emphasizing rational combination therapies to overcome drug resistance while preserving physiological homeostasis.