@cs3000

in response to stimulation with 1,25[OH]₂ D, upregulation of the inactivating enzyme CYP24A1 curtailed the functional effects of vitamin D in DCs, but not macrophages.

rifampin fixes 1,25 excess in sarcoidosis through inducing CYP 3a4 enzyme

So CYP 3a4 can be used to lower the 1,25 excess coming from macrophages

side note 24,25 vit D increases bone strength / fracture repair where 1,25 does not have this effect https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063485/

Insightful studies below that highlight 24,25 aka 24r,25 looks to be the commonly desirable form of vitamin D.
If in good health it's supposed to rise in ratio to 1,25 as 25 vit D goes up, https://www.nature.com/articles/s41598-019-43462-6

24r,25 form of vit D is likely protective in MS / brain atrophy https://pubmed.ncbi.nlm.nih.gov/21047880/ lower 24,25 compared to 25 = worse outcome

and it actually DECREASES the VD Receptor

Vitamin D3 is metabolized in the liver and kidney in addition to localized tissue-specific biosynthesis. Bone cells are known to metabolize 25(OH)D3 into both 1α,25(OH)2D3 and 24R,25(OH)2D3 via 1α-OHase and 24-OHase, respectively

24,25 DECREASES vdr expression and can lower 1,25,
it inhibits stem cell proliferation like 1,25 also does, but unlike 1,25 it stimulates stem cell maturation / enables their differentiation ,
increasing bone repair / strength https://pubmed.ncbi.nlm.nih.gov/24597546/

(but by my experience cannot get this increased enough simply through vit D without worsening the issue from extra 1,25 in people with this excess issue,
was thinking maybe there isnt enough 24a1 enzyme producing 24,25 here, but upregulating doesnt work to counter 1,25 in macrophages)

targeting less 1,25 through CYP 3a4 should have effect but also degrades 25 vit D though, so losing 24,25.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310418/

Thyroid hormone also increases cyp3a4
(another connection to hypothyroid & vitamin D problems)
and also decreases CYP27B1 , lowering 1,25 (at least in the kidneys, wonder if this also has effect in macrophages keratinocytes etc https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077994/table/T1/?report=objectonly)

lowering Cyp27b1 is a major target for lowering 1,25, it stays expressed even when macrophages are removed from IFN-y inducing environment https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077994/

How was it that synthetic 1-hydroxylating activity in macrophages harvested from humans with active disease persisted ex vivo in culture even in the absence of conditioning IFNs? Some of the questions have been answered and some are still coming to light. For example, it is now known that there exists a single gene that encodes the 1-hydroxylase, CYP27B1 [11] and the 24-hydroxylase, CYP24A1 [12]. Further, it is now clear that persistence of mTB in macrophages is an explanation for the continual expression of the CYP27B1 in human macrophages even after their removal from the host and conditioning cytokines present in the inflammatory microenvironment in the host.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508960/
(thyroid hormone & iron key players) & upping 24,25

In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvβ3 and the activation of signalling pathways through Stat1 and NF-κB.

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@cs3000 I can bear witness to this.

When I was suffering from a year long condition that started with bronchitis, my eyelids were drooping. The lack of the usual amount of oxygen easily translates into low energy. And my eyelids were a good tell.