These data suggest that in contrast to its detrimental effect in CLD mouse models with an underlying autophagy impairment, p62 plays a protective role against CLD progression in NEMOLPC-KO mice, and systemic p62 deficiency is synthetically lethal when combined with LPC-specific NEMO deficiency. The gene discussed is IKBKG; the disease is congenital secretory chloride diarrhea 1.