| Category | Key points | Quantitative data (if any) | Key sources (with citation IDs) |
|---|---|---|---|
| Protein type / localization | Human **HPX** (UniProt **P02790**) corresponds to **hemopexin**, a **secreted/plasma glycoprotein** and major extracellular heme scavenger. It is primarily produced by liver and is also reported in nervous tissue, skeletal muscle, retina, and kidney; HPX is present in plasma and also detected in CSF and lymph. | ~**60 kDa**; plasma concentration reported **0.4–1.5 mg/mL** or **0.5–1.5 mg/mL**; ≈**15.3 µM** average in one recent study/review synthesis. | (pqac-00000003, pqac-00000005, pqac-00000013) |
| Primary ligand / substrate | Primary ligand is **free heme** (including heme released during hemolysis and heme transferred from other plasma carriers). HPX is described as the **highest-affinity heme-binding protein in plasma** and a second-line defense after haptoglobin depletion. | Heme–HPX forms a **1:1 complex**; each mL plasma can bind **6.3 mg heme** according to a 2023 review summary. | (pqac-00000001, pqac-00000003, pqac-00000007, pqac-00000009) |
| Binding stoichiometry / concentration ranges | HPX binds heme tightly at physiologic pH and releases it in acidic endosomal compartments. At low heme, binding is 1:1; at higher heme loads, reports indicate **≥2:1 (heme:HPX)** binding behavior. | Stoichiometry: **1:1** at low heme; **≥2:1** at higher heme. Plasma HPX: **0.4–1.5 mg/mL** / **0.5–1.5 mg/mL**; one review cites average plasma HPX **770 mg/mL** but this value is likely inconsistent with the broader literature and should be treated cautiously. | (pqac-00000003, pqac-00000005, pqac-00000009, pqac-00000013) |
| Receptors / uptake pathways | Canonical pathway is **CD91/LRP1-mediated** uptake of heme–HPX in liver/macrophages. Recent cell work indicates uptake is not exclusively LRP1-dependent: HPX traffics with **transferrin receptor 1 (TfR1)** in **Rab5-positive early endosomes**, and **TfR2** may contribute to hepatic targeting; uptake also occurs in **LRP1−/−** cells, implying alternative receptors. | **LRP1 Kd ≈ 4 nM** for HPX binding; LRP1 described as a high-affinity HPX-binding protein. | (pqac-00000001, pqac-00000002, pqac-00000007, pqac-00000008) |
| Downstream intracellular fate / pathway | After endocytosis, heme is delivered intracellularly and induces a **cytoprotective program**: **HMOX1/HO-1 induction**, ferritin induction, transferrin receptor downregulation, metallothionein induction, and coupling to iron storage/export pathways. Heme degradation yields bilirubin, CO, and iron; iron is stored in ferritin or exported via ferroportin. Apo-HPX may recycle in some settings. | Free heme uptake can occur at ~**5-fold higher molar rate** than heme–HPX uptake; intracellular heme levels of **3 µM** (~**1 million heme molecules** in mitochondrial volume) were reported in hepatocyte-focused review literature. | (pqac-00000002, pqac-00000004, pqac-00000007) |
| Key disease contexts: SCD / hemolysis | HPX is depleted in hemolytic states including **sickle cell disease (SCD)**, where low HPX is linked to heme overload, vaso-occlusion, AKI risk, and priapism-related pathophysiology. Reviews note lower HPX in SCD vaso-occlusive crisis versus steady state and increases with hydroxycarbamide/hydroxyurea as hemolysis declines. | No exact cohort HPX concentration from the gathered 2024 SCD biomarker study excerpt; pediatric SCD study included **377 children** aged **3–8 years**. | (pqac-00000009, pqac-00000011, pqac-00000012, pqac-00000014) |
| Key disease contexts: sepsis / trauma / burn | In inflammatory/hemolytic injury states, HPX is often insufficient relative to heme burden. Major trauma and burns show elevated plasma heme with reduced hemopexin and albumin, supporting failure of the scavenging system and motivating HPX restoration concepts. | Trauma cohort: **147** patients (mean age **42**, mean ISS **25**). Burn cohort: **98** patients (mean age **47**, mean TBSA **35%**). Heme correlated with burn severity: %TBSA **r=0.456**, % full-thickness TBSA **r=0.466**, Baux **r=0.350**, revised Baux **r=0.390**; trauma heme vs time **r=-0.452**. | (pqac-00000015, pqac-00000016, pqac-00000018) |
| Key disease contexts: CNS hemorrhage | HPX is implicated in CNS blood-breakdown product handling. Review evidence indicates **CSF HPX** can associate with outcomes after intracranial hemorrhage, though direction differs by condition: better outcomes in some **ICH** contexts but worse in **SAH** in others. HPX is also discussed as protective in intracerebral hemorrhage models. | No consistent single quantitative effect size for HPX across CNS hemorrhage contexts in the gathered evidence. | (pqac-00000004, pqac-00000009) |
| Therapeutic / clinical translation | Translational strategies include **HPX supplementation** during endogenous depletion, **combined Hp+HPX** approaches, recombinant **rhHPX** production, **hemopexin–haptoglobin fusion proteins**, and **AAV-based HPX gene therapy** concepts. A **phase 1** study in sickle cell anemia is mentioned in review literature. | Clinical trial mention: **NCT04285827** (phase 1 HPX in sickle cell anemia, as cited in the 2023 review). AAV-mediated expression reported for **58 days** with survival after experimental heme challenge in preclinical work summarized by the review. | (pqac-00000009, pqac-00000010, pqac-00000013) |
| Quantitative findings from 2024 trauma/burn study | Burn/trauma study provides the clearest recent human quantitative evidence linking excess heme and depleted scavenging proteins. Hemopexin was significantly reduced on day 1/day 3 post-injury, though exact HPX concentrations were not reported in the extracted evidence. | Burns: day 3 heme **17.03 ± 0.92 µM** vs healthy controls **17.59 ± 1.47 µM** (ns). In burns, **6.5 µM** higher day-1 heme associated with sepsis odds **OR 1.24** (95% CI **1.05–1.46**, p=**0.013**), adjusted **OR 1.12** (0.95–1.33, p=**0.172**); mortality odds **OR 1.63** (1.12–2.37, p=**0.004**), adjusted **OR 1.52** (1.02–2.28, p=**0.021**). AUROC for mortality using day-1 heme: **0.768** (95% CI **0.615–0.922**) vs rBAUX **0.718**. Sepsis assessed in **79** burn patients; **42** developed sepsis (**53%**). | (pqac-00000015, pqac-00000016, pqac-00000017, pqac-00000018, pqac-00000019) |


*Table: This table summarizes the functional annotation of human HPX/hemopexin, emphasizing ligand binding, uptake pathways, intracellular fate, disease relevance, and recent translational findings. It is designed as a compact evidence map for narrative reporting and citation-supported interpretation.*