This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "er_protein_storage_disease#Hepatic Protein Aggregation"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should substitute the disorder-specific stored protein and gene (SERPINA1/Z-AAT for alpha-1 antitrypsin deficiency, FGG for hepatic fibrinogen storage disease) while preserving the conserved ER-retention → ER stress → hepatocyte injury → stellate-cell-mediated fibrosis chain. Reduced circulating levels of the affected secretory protein (e.g., hypofibrinogenemia, low serum AAT) are a secondary loss-of-secretion consequence handled in the disorder entries, not in this hepatocyte-toxicity module. Evidence here is drawn from the prototypical Z-AAT exemplar; it documents the conserved cascade rather than any single disease. This misfolding-retention-polymerization cascade is distinct from tsr_o_glycosylation_quality_control, which stabilizes correctly folded TSR domains and selectively affects their secretion without requiring ER storage.
Hepatic Protein Aggregation
trigger
A mutant secretory protein misfolds during biogenesis in the hepatocyte and a large fraction (e.g., ~85% of Z-AAT in the PiZZ genotype) is retained within the endoplasmic reticulum rather than being secreted. The retained protein adopts ordered polymerized or aggregated conformations forming intracellular inclusions, leaving the circulating protein deficient while imposing a proteotoxic burden on the hepatocyte.
Downstream
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ER Stress and Unfolded Protein Response
Intracellular accumulation of misfolded/polymerized protein imposes proteotoxic stress on the ER, activating ER stress responses.
ER Stress and Unfolded Protein Response
amplifier
Accumulation of misfolded and polymerized protein in the ER lumen imposes sustained proteotoxic stress, activating the unfolded protein response and ER-overload signaling. ER-associated degradation and autophagic clearance are progressively saturated, sustaining and amplifying the cellular stress state.
Downstream
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Hepatocyte Injury
Sustained ER stress and saturation of degradative clearance drive hepatocyte death.
Hepatocyte Injury
effector
Sustained ER stress and the intracellular polymer burden trigger mitochondrial depolarization and caspase-mediated apoptosis, with saturation of autophagic clearance and redox injury, producing chronic hepatocyte death and compensatory regeneration.
Downstream
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Stellate Cell Activation and Fibrosis
The chronic cycle of hepatocyte death and regeneration activates hepatic stellate cells and initiates fibrosis.
Stellate Cell Activation and Fibrosis
central effector
The chronic cycle of hepatocyte death and compensatory regeneration activates quiescent hepatic stellate cells, which transdifferentiate into collagen-producing myofibroblasts under TGF-beta signaling. Progressive collagen deposition drives bridging fibrosis and cirrhosis. This terminal step conforms to the conserved fibrotic response: the hepatic stellate cell is the organ-specific substitution for the generic activated mesenchymal cell.