Introduction: Hepatic stellate cells (HSCs) are responsible for collagen deposition leading to fibrosis following liver injury/inflammation. Serum ferritin levels reflect body iron stores in haemochromatosis and are elevated in inflammation where they act as an indicator of disease severity in chronic liver disease. We have previously demonstrated that H-subunit ferritin (FTH1) actually contributes to this process as a pro-inflammatory mediator in HSC biology via an iron-independent, NFkappaB-regulated signalling pathway, inducing the expression of cytokines, e.g., IL-1β. The signalling receptor responsible for the effect of FTH1 on HSC-induced inflammation remains unknown. Aims: To characterize the FTH1 receptor and underlying molecular mechanisms responsible for proinflammatory cytokine stimulation in HSCs. Methods: In order to identify the FTH1 receptor, primary rat HSCs were exposed to 10nM FTH1 for 2hrs at 4oC vs 37oC and cell extracts were subjected to immunoprecipitation of FTH1-binding proteins with subsequent analysis by mass spectrometry. This identified numerous potential candidate molecules. Validation of potential FTH1 receptor candidates included analysis of IL-1β mRNA/protein expression by qPCR/Western blot following i) gain- and loss-of function experiments; and ii) disruption of plasma membrane-endocytic signaling/trafficking pathways using specific inhibitors (i.e.,clathrin-coated pit endocytosis via PitStop). In addition, we examined iii) the reciprocal regulation between FTH1-signalling and components of the inflammasome by western-blotting, immunofluorescence, qRT-PCR and ELISA; and iv) determination of the potential for FTH1 to stimulate proinflammatory cytokine synthesis in whole liver using an ex vivo precision-cut liver slice tissue culture model. Results: This study revealed QIMR1 (de-identified, as subject of a pending patent application) as a novel H-Ferritin signaling receptor candidate in HSCs. Accordingly, transfection of primary rat HSCs with QIMR1 siRNA (which achieved 77% QIMR1 knock-down, p=0.023), significantly inhibited FTH1-induced IL-1β mRNA expression by 60% (p=0.00021), while over-expression of QIMR1 exacerbated the FTH1-induced IL-1β transcripts by 70% (p=0.028). Maturation of active IL-1β protein is mediated by NLRP-associated proteins within the inflammasome. Western-blot analysis demonstrated that FTH1 stimulates NLRP3, but not NLRP1, protein levels in HSCs and that this is prevented via inhibition of clathrin-coated pit endocytosis. We also showed that FTH1 induced the expression of active Caspase-1 protein and active IL-1β protein secretion. FTH1-induced expression of NLRP3 was prevented by knock-down of QIMR1. Finally, as a proof of concept that FTH1 has the ability to influence liver tissue inflammation, we have demonstrated that FTH1 stimulates IL-1β mRNA expression (~3 fold; p=0.033) in precision-cut (ex-vivo) liver slices. Conclusions: We have characterized a novel FTH1 receptor (QIMR1) that is responsible for the transduction of FTH1-induced proinflammatory signalling, resulting in NLRP3-dependent inflammasome activation and IL-1β secretion in HSCs. This process is dependent on clathrin-coated pit endocytosis. Therefore, this study provides the first evidence of a role for FTH1-induced signaling via QIMR1 in HSCs as a unique molecular mechanism for the promotion of hepatic inflammation in chronic liver disease.