SIRT2-ANXA2 Axis in Donafenib Resistance: Promising Mechanistic Insight Demands Contextual and Translational Scrutiny

In their seminal study, Sun et al. delineate a novel pathway wherein SIRT2-mediated deacetylation of ANXA2 promotes protective autophagy, thereby conferring resistance to donafenib in hepatocellular carcinoma (HCC). This work provides a compelling mechanistic explanation for a significant clinical challenge. Our letter offers a prospective critique of these findings. We posit that while the SIRT2-ANXA2-ATG4B axis represents a bona fide therapeutic target, its clinical translation necessitates a more nuanced appraisal. Key considerations include the context-dependent duality of SIRT2 as both an oncogene and tumor suppressor, which may dictate heterogeneous responses across HCC etiologies. Furthermore, the biochemical mechanism linking ANXA2 deacetylation to enhanced autophagic flux warrants deeper interrogation, particularly regarding the functional impact on ATG4B protease activity. Finally, we emphasize the paramount importance of evaluating the therapeutic index of combining donafenib with SIRT2 or autophagy inhibition, as potential on-target toxicities in normal tissues could limit clinical applicability. Future efforts should focus on defining predictive biomarkers for patient stratification. In conclusion, the study by Sun et al. opens crucial new avenues; however, overcoming the outlined challenges is essential for harnessing this knowledge into effective therapeutic strategies.