Inhibition of dipeptidyl peptidase 7 impairs lysophagy in LLOMe-treated HepG2 cells

Lysophagy selectively eliminates damaged lysosomes to preserve lysosomal homeostasis, but its regulatory mechanisms remain incompletely understood. Here, we identify dipeptidyl peptidase 7 (DPP7), a lysosomal serine protease, as a regulator of lysophagy. Inhibition or depletion of DPP7 impaired clearance of LLOMe-damaged lysosomes in HepG2 cells, as evidenced by sustained galectin-3 puncta and reduced lysophagic flux. DPP7 inhibition did not block TFEB activation; however, it markedly reduced ubiquitin accumulation on damaged lysosomes and attenuated the recruitment of SQSTM1 and LC3. This defect was accompanied by impaired lysosomal re-acidification and reduced maturation of cathepsin D and L. Together, our findings identify DPP7 as a novel modulator of ubiquitin-dependent lysophagy and reveal an unexpected role for a lysosomal peptidase in lysosomal quality control.