How Aging Liver Cells Hijack Fat Storage to Drive Disease Progression

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called NAFLD, now affects over one-third of adults worldwide and represents the leading cause of chronic liver disease. While it often begins as simple hepatic steatosis, roughly 15% of patients progress to the inflammatory stage (MASH), and up to 30% of those develop fibrosis, cirrhosis, or hepatocellular carcinoma. Despite its prevalence, the precise mechanisms linking fat accumulation to disease advancement remain incompletely understood. This review addresses a critical gap by integrating two previously siloed fields: cellular senescence biology and hepatic lipid metabolism.

The authors frame cellular senescence (CS) as a multistage process—early, full, and late—driven by both replicative telomere shortening and stress-induced premature senescence (SIPS). Key pathways include p53-p21 and p16INK4α-Rb cascades. A hallmark of senescent cells is the senescence-associated secretory phenotype (SASP), a dynamic secretome including IL-1, IL-6, IL-8, MCP-1, HGF, and matrix metalloproteinases. SASP evolves in phases: an initial adaptive, reparative phase; a self-amplifying inflammatory phase; and ultimately a stable late-SASP state that promotes chronic inflammation, tumor formation, and aging. NF-κB is identified as a central regulator of pro-inflammatory SASP components, while mTOR stabilizes SASP mRNA expression.

A critical mechanistic insight of this review concerns the role of CD36, a membrane fatty acid receptor that is rapidly upregulated upon CS onset. This upregulation initially serves to increase lipid uptake—fueling elevated energy demands and membrane remodeling in enlarged senescent cells. It also activates NF-κB, which in turn drives SASP formation. Early in senescence, elevated free fatty acid influx can activate PPARα, promoting fatty acid oxidation (FAO) as a compensatory response. However, as senescence persists, mitochondrial dysfunction develops, FAO is progressively suppressed, and excess fatty acids are shunted into lipid droplets, worsening hepatic steatosis.

Rather than treating lipid droplets as passive storage organelles, the review emphasizes their active role in cellular signaling. LDs interact with mitochondria, endoplasmic reticulum, and peroxisomes to regulate lipid flux and energy balance. Key LD-associated proteins such as perilipins (PLINs) regulate lipid release and organelle cross-talk. Disruption of LD homeostasis feeds back into senescence-associated signaling, creating a self-reinforcing loop that amplifies both lipid accumulation and the SASP inflammatory milieu. Additionally, senescent cells release lipid-enriched extracellular vesicles that propagate inflammatory signals to neighboring cells, with IL-1 capable of inducing paracrine senescence in adjacent hepatocytes.

The authors highlight fatty acid synthase (FASN) as a key early enzyme whose upregulation supports membrane biogenesis and SASP secretion in early senescent cells—and whose inhibition attenuates SASP. Up to 80% of hepatocytes may become senescent in advanced MASLD, representing an enormous disease burden. The review concludes that targeting the CS–LD feedback axis—through senolytics, senomorphics, or metabolic interventions—could represent a disease-modifying approach in MASLD, though the authors caution that most mechanistic evidence derives from non-hepatic in vitro systems or animal models, with limited direct human liver disease data.