Non-histone lysine lactylation: Emerging roles in tumor biology and therapeutic implications

Lactate, a byproduct of glycolysis, was first identified to induce a novel post-translational modification (PTM) known as lysine lactylation (Kla) in 2019. Kla has been shown to regulate various biological processes, including transcription, metabolism, cell proliferation, and inflammatory responses, which are pivotal in both tumorigenesis and cellular aging. Initially, Kla was identified as an epigenetic marker on histones, where it regulates gene transcription. However, more recent studies have demonstrated widespread Kla modifications on non-histone proteins, suggesting their involvement in multiple tumorigenic processes, which are often dysregulated during aging. Unlike histone Kla, which influences gene accessibility and transcription, non-histone protein Kla exerts a more direct influence on protein levels and functions by modifying their stability, activity, or localization. This review summarizes the latest advances in non-histone Kla research, highlighting its regulatory factors and role in tumor biology and treatment resistance. Additionally, we discuss the potential implications of non-histone Kla in tumor diagnosis, prognosis, and targeted therapy.